Fasten Onco Digital Therapy During Neoadjuvant Treatment for Triple-Negative Breast Cancer

• Fasten Onco (Device): Fasten Onco is a digital medical device designed to support the implementation of a fasting-mimicking diet (FMD) during neoadjuvant treatment. The device provides a personalized nutritional program synchronized with the participant's treatment schedule, together with educational content, reminders, and guidance to support adherence. The program is prescribed and configured by a healthcare professional and is used under medical supervision.
• Standard Neoadjuvant Treatment (Drug): Standard neoadjuvant treatment for stage II/III triple-negative breast cancer according to the standard of care at each participating center. Treatment may include paclitaxel, carboplatin, epirubicin or doxorubicin, cyclophosphamide, and pembrolizumab, used within their approved indications. Standard neoadjuvant treatment is administered in both study groups.

Primary outcomes

• Change From Baseline in FACIT-Fatigue Total Score [Baseline to Day 7 after initiation of Cycle 8 of neoadjuvant treatment]: Absolute change from baseline in the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) total score. The FACIT-Fatigue is a 13-item questionnaire assessing fatigue and its impact on daily activities and functioning. The total score ranges from 0 to 52, with higher scores indicating less fatigue and better functioning. The primary comparison will assess the difference in change from baseline between the FASTEN Group and the Standard of Care Group.

Secondary outcomes

• Change From Baseline in FACIT-Fatigue Total Score and Subscores Over the Neoadjuvant Treatment Period [Baseline through Day 7 after initiation of Cycle 8; cycles are generally scheduled every 3 weeks]: Absolute change from baseline in the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) total score and subscores during the neoadjuvant treatment period. The FACIT-Fatigue is a 13-item questionnaire with a total score ranging from 0 to 52, with higher scores indicating less fatigue and better functioning.
• Time to Definitive Fatigue Worsening [From randomization through study completion, up to 3 years]: Time from randomization to the first deterioration of ≥6 points out of 52 in the FACIT-Fatigue total score compared with baseline, with no subsequent improvement or deterioration <6 points until the end of the study, or in a participant who drops out after a ≥6-point decrease resulting in missing data or death.
• FACIT-Fatigue Severity Category [Baseline through Day 7 after initiation of Cycle 8; cycles are generally scheduled every 3 weeks]: FACIT-Fatigue severity categorized as severe (total score ≤34) or non-severe (total score >34), including shifts from baseline. The Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) is a 13-item questionnaire with a total score ranging from 0 to 52, with higher scores indicating less fatigue and better functioning.
• Change From Baseline in FACT-G Total Score at Cycle 8 [Baseline to Day 7 after initiation of Cycle 8; cycles are generally scheduled every 3 weeks]: Absolute change from baseline in the Functional Assessment of Cancer Therapy-General (FACT-G) total score. The FACT-G is a 27-item questionnaire assessing physical, social/family, emotional, and functional well-being. The total score ranges from 0 to 108, with higher scores indicating better quality of life.
• Change From Baseline in FACT-G Total Score Over the Neoadjuvant Treatment Period [Baseline through Day 7 after initiation of Cycle 8; cycles are generally scheduled every 3 weeks]: Absolute change from baseline in the Functional Assessment of Cancer Therapy-General (FACT-G) total score during the neoadjuvant treatment period. The FACT-G is a 27-item questionnaire assessing physical, social/family, emotional, and functional well-being. The total score ranges from 0 to 108, with higher scores indicating better quality of life.
• Change From Baseline in FACT-G Domain Scores at Cycle 8 [Baseline to Day 7 after initiation of Cycle 8; cycles are generally scheduled every 3 weeks]: Absolute change from baseline in the four Functional Assessment of Cancer Therapy-General (FACT-G) domain scores: Physical Well-Being (0 to 28), Social/Family Well-Being (0 to 28), Emotional Well-Being (0 to 24), and Functional Well-Being (0 to 28). Higher scores indicate better well-being.
• Change From Baseline in FACT-G Domain Scores Over the Neoadjuvant Treatment Period [Baseline through Day 7 after initiation of Cycle 8; cycles are generally scheduled every 3 weeks]: Absolute change from baseline in the four Functional Assessment of Cancer Therapy-General (FACT-G) domain scores during the neoadjuvant treatment period: Physical Well-Being (0 to 28), Social/Family Well-Being (0 to 28), Emotional Well-Being (0 to 24), and Functional Well-Being (0 to 28). Higher scores indicate better well-being.
• Time to Definitive FACT-G Deterioration [From randomization through study completion, up to 3 years]: Time from randomization to the first deterioration of ≥5 points out of 108 in FACT-G total score compared with baseline, with no subsequent improvement or deterioration <5 points until the end of the study, or in a participant who drops out after a ≥5-point decrease resulting in missing data or death.
• Time to Definitive FACT-G Subscore Deterioration [From randomization through study completion, up to 3 years]: Time from randomization to the first deterioration of ≥3 points in a FACT-G subscore compared with baseline, with no subsequent improvement or deterioration <3 points until the end of the study, or in a participant who drops out after a ≥3-point decrease resulting in missing data or death.
• Evolution of FACIT-Fatigue and FACT-G Scores and Subscores [Baseline through study completion, up to 3 years]: Evolution of the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) total score and subscores and the Functional Assessment of Cancer Therapy-General (FACT-G) total score and domain scores during the study, including assessments before and after surgery. The FACIT-Fatigue total score ranges from 0 to 52, with higher scores indicating less fatigue and better functioning. The FACT-G total score ranges from 0 to 108, with higher scores indicating better quality of life.
• Incidence of Adverse Events [During treatment through 28 days after the last dose]: Incidence of adverse events graded according to NCI-CTCAE v5.0, including all AEs, grade ≥3 toxicities, treatment-related AEs, grade ≥3 neutropenia, SAEs, grade ≥3 hematological toxicities, related SAEs, and adverse device effects.
• Pathological Complete Response [At surgery]: Pathological complete response (pCR) assessed at surgery.
• Net Treatment Benefit [From baseline through surgery following completion of neoadjuvant treatment, assessed up to approximately 30 weeks.]: Net treatment benefit assessed using generalized pairwise comparisons based on prioritized outcomes: Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) total score (range 0 to 52, with higher scores indicating less fatigue and better functioning), Functional Assessment of Cancer Therapy-General (FACT-G) total score (range 0 to 108, with higher scores indicating better quality of life), grade ≥3 neutropenia, and pathological complete response.
• Change From Baseline in Body Weight [Baseline through study completion, up to 3 years]: Absolute change from baseline in body weight, measured in kilograms (kg), during the study, including changes during and between Fasten Onco active fasting-mimicking diet days.
• Event-Free Survival [From randomization through study completion, up to 3 years]: Time from randomization to the first occurrence of disease relapse or death from any cause.
• Overall Survival [From randomization through study completion, up to 3 years]: Time from randomization to death from any cause.
• Change From Baseline in FACT-Cog Score and Subscores [Baseline to end of neoadjuvant phase and 12 months after end of neoadjuvant phase]: Absolute change from baseline in the Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog), Version 3, total score and subscale scores. The FACT-Cog assesses four domains: Perceived Cognitive Impairments, Impact of Perceived Cognitive Impairments on Quality of Life, Comments from Others, and Perceived Cognitive Abilities. Using the recommended 33-item scoring algorithm, the total score ranges from 0 to 132, with higher scores indicating better perceived cognitive functioning.
• Unscheduled Medical Events [From randomization through study completion, up to 3 years]: Number of days of unscheduled hospitalization, number of unscheduled hospitalizations, and number of emergency consultations.
• Duration of Neoadjuvant Treatment Exposure [From first administration of Cycle 1 through last administration of Cycle 8; cycles are generally scheduled every 3 weeks]: Duration in days from the first administration to the last administration of neoadjuvant treatment.
• Blood Glucose Levels During Fasting-Mimicking Diet Cycles [Baseline and before and after each 4-day FMD cycle, from Cycle 1 through Cycle 8]: Blood glucose levels measured by participant self-monitoring at baseline and before and after each fasting-mimicking diet (FMD) cycle.
• Adverse Events Related to the FASTEN Intervention [From initiation of the FASTEN intervention at Cycle 1 through completion of Cycle 8 of neoadjuvant treatment (treatment cycles generally administered every 21 days; approximately 24 weeks).]: Incidence of adverse events related to the FASTEN intervention, as assessed by the investigator and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 5.0.
• Patient Satisfaction With Fasten Onco [After completion of the third Fasten Onco cycle and at completion of Fasten Onco use following Cycle 8 of neoadjuvant treatment (treatment cycles generally administered every 21 days; approximately 24 weeks).]: Patient satisfaction with Fasten Onco assessed using a study-specific 5-point Likert scale ranging from 0 (very dissatisfied) to 4 (very satisfied), with higher scores indicating greater satisfaction.
• Prognostic Factors for Event-Free Survival [From randomization through study completion, up to 3 years]: Assessment of the association between prognostic factors and event-free survival (EFS). Prognostic factors evaluated include age, body mass index (BMI), disease stage, node status, tumor-infiltrating lymphocytes at baseline and surgery, Ki-67 grade and proliferation at baseline and surgery, and other identified prognostic factors.
• Tumor-Infiltrating Lymphocytes [Baseline and surgery, when available]: Evolution of tumor-infiltrating lymphocyte levels during the study, when available.
• Change From Baseline in Body Mass Index [Baseline through study completion, up to 3 years]: Absolute change from baseline in body mass index (BMI), measured in kilograms per square meter (kg/m²), during the study, including changes during and between Fasten Onco active fasting-mimicking diet days.
• Cumulative Administered Dose of Neoadjuvant Treatment [From Cycle 1 through Cycle 8; cycles are generally scheduled every 3 weeks]: Total administered dose of neoadjuvant treatment received by each participant during the neoadjuvant treatment period.

Other outcomes

• Dose Intensity of Neoadjuvant Treatment [From Cycle 1 through Cycle 8; cycles are generally scheduled every 3 weeks]: Dose intensity calculated as the total administered dose as a proportion of the total planned dose.
• Number of Neoadjuvant Treatment Cycles Received [From Cycle 1 through Cycle 8; cycles are generally scheduled every 3 weeks]: Number of neoadjuvant treatment cycles received by each participant.
• Number of Neoadjuvant Treatment Dose Delays [From Cycle 1 through Cycle 8; cycles are generally scheduled every 3 weeks]: Number of dose delays occurring during neoadjuvant treatment.
• Neoadjuvant Treatment Discontinuation [From Cycle 1 through Cycle 8; cycles are generally scheduled every 3 weeks]: Number of participants who permanently discontinue neoadjuvant treatment before planned completion. Reasons for discontinuation will be recorded.
• Blood Ketone Levels During Fasting-Mimicking Diet Cycles [Baseline and before and after each 4-day FMD cycle, from Cycle 1 through Cycle 8]: Blood ketone levels measured by participant self-monitoring at baseline and before and after each fasting-mimicking diet (FMD) cycle.
• Proportion of Fasting-Mimicking Diet Cycles Completed [From Cycle 1 through Cycle 8; each FMD cycle lasts 4 days]: Proportion of fasting-mimicking diet (FMD) cycles completed relative to the number of neoadjuvant treatment cycles received by each participant.
• Duration of Fasten Onco Application Use [From initiation of Fasten Onco at Cycle 1 through completion of Cycle 8 of neoadjuvant treatment (treatment cycles generally administered every 21 days; approximately 24 weeks).]: Duration of use of the Fasten Onco application by each participant, measured in days.
• Time Spent Using the Fasten Onco Application [From Cycle 1 through completion of Cycle 8 of neoadjuvant treatment (treatment cycles generally administered every 21 days; approximately 24 weeks).]: Total time spent using the Fasten Onco application by each participant during the neoadjuvant treatment period, measured in minutes.
• Accuracy of Fasten Onco Synchronization With Neoadjuvant Treatment [From Cycle 1 through Cycle 8 of neoadjuvant treatment (treatment cycles generally administered every 21 days; approximately 24 weeks).]: Proportion of Fasten Onco fasting-mimicking diet cycles correctly synchronized with the corresponding neoadjuvant treatment cycles.
• Investigator Satisfaction With Fasten Onco [At completion of Cycle 8 for the last participant at each study center (treatment cycles generally administered every 21 days; approximately 24 weeks after Cycle 1 for that participant).]: Investigator satisfaction with Fasten Onco assessed using a 5-point Likert scale ranging from 0 (very dissatisfied) to 4 (very satisfied), with higher scores indicating greater satisfaction.
• Time Required for Patient Registration in Fasten Onco [At baseline, during initial participant registration in Fasten Onco, before initiation of Cycle 1.]: Time spent by the oncologist to register a participant in Fasten Onco.
• Usability of Fasten Onco Assessed With the French System Usability Scale [After completion of the third Fasten Onco cycle (approximately 9 weeks after initiation, if aligned with the 21-day neoadjuvant treatment cycles)]: Usability of Fasten Onco assessed using the French version of the System Usability Scale (F-SUS). The F-SUS consists of 10 items and provides a total score ranging from 0 to 100, with higher scores indicating better perceived usability.
• Prognostic Factors for Overall Survival [From randomization through study completion, up to 3 years]: Assessment of the association between prognostic factors and overall survival (OS). Prognostic factors evaluated include age, body mass index (BMI), disease stage, node status, tumor-infiltrating lymphocytes at baseline and surgery, Ki-67 grade and proliferation at baseline and surgery, and other identified prognostic factors.

Sex: Female, ages: 18 Years to any

Inclusion Criteria:

* \- Patient has provided written informed consent before participating in the trial.
* Women aged ≥18 years.
* Patient with documented diagnosis of stage II/III triple negative breast cancer (TNBC) as per ESMO guidelines.
* Patient with Eastern Cooperative Oncology Group (ECOG) performance status ≤2.
* Patient has adequate bone marrow function.
* Patient has adequate renal function.
* Patient has adequate liver function.
* Patient has adequate heart function, i.e., no signs of heart failure or clinically significant arrhythmia.
* Patient has completed the FACIT-Fatigue and FACT-G questionnaires at baseline.
* Patient has access to a smart phone with access to the internet.
* Patient with a weighing scale to measure weight.
* Patient is able and willing to complete the trial, including the assigned questionnaires.
* Patient can read and write in French.
* Patient is covered by the French social security insurance or a similar healthcare insurance.

Exclusion Criteria:

* Persons referred to in Articles L1121-5 to L1121-8 of the Public Health Code (covering all protected persons: pregnant women, women in labour, breastfeeding mothers, persons deprived of their liberty by judicial or administrative order, minors, and persons subject to a legal protection measure: guardianship or curatorship).
* Patient with prior breast cancer (invasive or non-invasive breast cancer).
* Patient with a history of cancer within the last 5 years, except for basal cell carcinoma of the skin or pre-invasive carcinoma of the cervix.
* Patient diagnosed with type I or II diabetes and treated.
* Patient with a body mass index (BMI) <18.5 kg/m² or patients with a BMI between 18.5 kg/m² and 20 kg/m² and weight loss ≥5% in the last 3 months or if a BMI >20 kg/m² and weight loss >10% in last 3 months.
* Patient with food allergies.
* Patient with metabolic disorders affecting gluconeogenesis or adaptation to short periods of fasting.
* Patient already treated with a chronic immunosuppressive drug (dexamethasone used according to SOC is permitted) >10 mg per day of prednisone or equivalent at study entry.
* Previous episodes of symptomatic hypotension leading to loss of consciousness.
* Previous episodes of symptomatic hypoglycemia.
* Patient with behavioral eating disorders.
* Patient already following a fasting or fasting mimicking diet.
* Use of herbal preparations or medications interfering with chemoimmunotherapy pharmacokinetics: St. John's wort, kava, ephedra (ma huang), gingko biloba, aloe vera (and its derivatives), artemisinin (and its derivatives), and dehydroepiandrosterone (DHEA).
* Use of vitamins or food supplements exceeding one-tenth (1/10) of the daily recommended dose except for vitamin D or containing calories.
* Use of any supplement or product with unknown chemical composition.
* Use of pharmacological agents known to interfere with fatigue assessment …
* Use of nutraceutical agents known to interfere with fatigue assessment …
* Agents interfering with FMD and metabolic pathways …
* Patient with medical or psychological condition, in the opinion of the investigator, preventing her from determining the study or giving meaningful informed consent.
* Patient participating in another interventional trial within 30 days prior to randomization.

• Lorène Seguin, MD, Principal investigator, Institut Paoli-Calmettes