Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Rare Diseases

Breast Neoplasms

Melanoma

Melanoma, Cutaneous Malignant

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Neoplasms

Skin Diseases

Neuroendocrine Tumor

Neuroepithelioma

The intervention consists in 5-day FMD (Fasting Mimicking Diet) to be followed for one cycle (Cohorts A and B) or for 4 consecutive every-four week cycles postoperatively.

The Fasting Mimicking Diet (or FMD) consists in a 5-day plant-based, low-calorie (about 600 Kcal on day 1, followed by about 300 KCal/day on days 2 to 5), low-carbohydrate low-protein diet

Filippo De Braud, Professor

Claudio Vernieri, MD

Claudio Vernieri, M.D., Ph.D.

This trial aims to assess the immunological and metabolic changes induced by the Fasting Mimicking Diet (FMD) in the pre-operative and post-operative setting in breast cancer and melanoma patients. Three cohorts of patients will be enrolled: 1) Cohort A: patients with resectable breast cancer (cT1N0M0 stage or cT1cN1M0-cT2cN0M0 stages not requiring pre-operative systemic treatment at the judgment of the investigator) who are candidate to curative surgery; 2) Cohort B: patients with malignant melanoma patients candidate to dissection of the lymph node basin because of a positive sentinel lymph node (stage IIIA-IIIB-IIIC); 3) Cohort C: patients with resected malignant melanoma (including radicalization and, in case, lymph node dissection) who are not candidate to any adjuvant treatment, but only to clinical and radiological follow-up (stage IIB-IIC). Patients in cohorts A and B will undergo one 5-days FMD cycle about 13-15 days before surgical removal of primary tumor (breast) or lymph nodes (breast, melanoma). Patients in cohort C will undergo 4 consecutive FMD cycles every 28 days, starting one month after surgery.

Preclinical evidences suggest that reducing the concentration of blood metabolites and growth factors reduces the in vivo growth of several tumor models, while protecting normal tissues from the cytotoxic effects of chemotherapeutical treatments. In recent years, a plant-based, calorie-restricted, low-carbohydrate, low-protein diet, also known as Fasting Mimicking Diet (FMD), has been proposed as a potential anticancer dietary intervention. The FMD is safe when administered cyclically (every 21-28 days) to healthy volunteers, and is capable of significantly reducing the concentration of plasma glucose, serum insulin and IGF-1, while increasing levels of plasma IGFBPs and ketone bodies. The FMD has been shown to inhibit the in vivo growth of several tumor models, including breast cancer and melanoma mice models. The anticancer effects of the FMD are likely mediated by two concomitant mechanisms: 1) one direct anticancer effect that is mediated by the inhibition of energy production and anabolic pathways, such as protein and fatty acid synthesis, in cancer cells; 2) one indirect effect that is mediated by the activation of antitumor immunity, with the result of enhanced tumor infiltration by cytotoxic CD8+ T-lymphocytes and reduced infiltration by immunosuppressive populations. According to the currently accepted model, the anticancer and immunomodulatory effects of the FMD mostly derive from the reduction of circulating glucose, insulin and IGF-1 levels, and a parallel increase of ketone body and IGF-1 binding protein concentration. However, recent observations in healthy volunteers and cancer patients, suggest that FMD-mediated changes in many other metabolites, such as specific amino acids or fatty acids, could contribute to the cell-autonomous or immune-mediated anticancer effects of the FMD. While the study of the effects of the FMD in combination with standard treatments (e.g. chemotherapy, molecular targeted therapy) in advanced cancers represents the final objective of the ongoing studies, fully uncovering the metabolic and immunological effects of the FMD alone is essential to design future combination studies. From this perspective, the pre- and post-operative clinical settings in cancer patients who are not candidate to other medical treatments represent an ideal context to assess the effects of the FMD without other confounding factors. This trial primarily aims to assess the immunological and metabolic changes induced by the FMD in the pre-operative and post-operative setting in breast cancer and melanoma patients. Three cohorts of patients will be enrolled: 1) Cohort A: patients with resectable breast cancer (cT1N0M0 stage or cT1cN1M0-cT2cN0M0 stages not requiring pre-operative systemic treatment at the judgment of the investigator) who are candidate to curative surgery; 2) Cohort B: patients with malignant melanoma patients candidate to dissection of the lymph node basin because of a positive sentinel lymph node (stage IIIA-IIIB-IIIC); 3) Cohort C: patients with resected malignant melanoma (including radicalization and, in case, lymph node dissection) who are not candidate to any adjuvant treatment, but only to clinical and radiological follow-up (stage IIB-IIC). Patients in cohorts A and B will undergo one 5-days FMD cycle about 13-15 days before surgical removal of primary tumor (breast) or lymph nodes (breast, melanoma). Patients in cohort C will undergo 4 consecutive FMD cycles every 28 days, starting one month after surgery.

Clinical trials with a single arm and three cohorts of patients

Impact of Dietary Intervention on Tumor Immunity: the DigesT Trial

Impact of Dietary Intervention on Tumor Immunity: the DigesT Trial.

Absolute and relative changes in PBMCs by 10-color cytofluorimetry before and after the FMD.

Phenotypic modifications in PBMCs, as detected by by 10-colors citofluorimetry and single-cell "mass cytometry" (CyTOF)

Functional modifications in PBMCs, as detected by by 10-colors citofluorimetry and single-cell "mass cytometry" (CyTOF)

Functional modifications in tumor-infiltrating lymphocytes, as detected by by 10-colors citofluorimetry and single-cell "mass cytometry" (CyTOF)

Phenotypic modifications in tumor-infiltrating lymphocytes, as detected by by 10-colors citofluorimetry and single-cell "mass cytometry" (CyTOF)

Functional modifications of immune cell populations in LNs, as detected by single-cell "mass cytometry" (CyTOF).

Gene expression profiling (through mRNA quantification) in tumor cells (Cohort A).

Gene expression profiling (through mRNA quantification) in PBMCs and immune cell populations inside lymph nodes (Cohort B).

miRNA profiling in tumor cells (Cohort A)

miRNA profiling in PBMCs and immune cell populations inside lymph nodes (Cohort B).

Changes in the expression of selected metabolic genes (including hexokinase 1, phosphofructokinase 1, pyruvate kinase 2) through mRNA quantification in PBMCs before and after the FMD.

FMD-induced changes in blood (glucose, triglycerides, fatty acids, cholesterol, amino acids)

FMD-induced changes in urine metabolites (ketone bodies)

FMD-induced changes in serum growth factors.

Qualitative changes in the type of tumor-infiltrating immune cell populations before and after the diet in breast cancer patients undergoing curative surgery (Cohort A).

Quantitative changes in the number of tumor-infiltrating lymphocytes, machrophages, MDSCs before and after the diet in breast cancer patients undergoing curative surgery (Cohort A).

Changes in tumor proliferation index (Ki67) IHC in breast cancer patients (Cohort A).

Changes in tumor cell apoptosis (caspase 3 by IHC) in breast cancer patients (Cohort A).

Changes in tumor levels of glycolytic enzymes by IHC (Glut1, HK1, PFK1/2, PK2) in breast cancer patients (Cohort A).

Changes in expression of estrogen and/progesterone receptor and HER2 oncoprotein by IHC in breast cancer patients (Cohort A).

Changes in the type of immune cells (CD8+ T-lymhocytes, CD 4+ lymphocytes, Treg) found in lymph node suspensions of melanoma patients undergoing one FMD cycle before lymph node dissection (Cohort B).

Quantitative changes in the absolute and relative amount of immune cell populations in lymph node suspensions of melanoma patients undergoing one FMD cycle before lymph node dissection (Cohort B).

Changes in genome-wide DNA methylomic profiles with high-density arrays in lymph node specimens from patients undergoing the FMD before surgery (Cohorts A and B).

Changes in genome-wide DNA methylomic profiles with high-density arrays in tumor specimens from patients undergoing the FMD before surgery (Cohorts A and B).

Changes in type of gut bacteria populations, as detected through 16S ribosomal RNA sequencing

Short-term (before vs after each FMD cycle) modification of blood nutritional parameters (levels of plasma cholesterol, prealbumin, transferrin, total lymphocytes)

Long-term (along subsequent FMD cycles) modification of blood nutritional parameters (levels of plasma cholesterol, realbumin, transferrin, total lymphocytes)

Short-term and long-term modification of BMI

FMD-induced changes in neutrophils, macrophages, lymphocytes

Assessment of patient compliance to the FMD, as measured by quantifying the number of major and minor deviations of patients' diet relative to the prescribed FMD scheme

Assessment of FMD tolerability, as defined by the occurrence of G3-G4 adverse events, or serious adverse events (SAEs)

Correlation between FMD-induced changes in serum metabolites and changes in PBMCs, their activation status, and characteristics of tumor cell and immune infiltrate.

Correlation between FMD-induced metabolic and immunological changes with patient diet evaluated at study enrollment through food diaries.

National Health Research Institutes, Taiwan

Centro de Investigación en Nanomateriales y Nanotecnología (CINN)

Institut National de la Santé Et de la Recherche Médicale, France

Martin-Luther-Universität Halle-Wittenberg

University of Milan

Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

Professor

Respiratory Tract (Lung and Bronchial) Diseases

Symptoms and General Pathology

Nutritional and Metabolic Diseases

Gland and Hormone Related Diseases

Nervous System Diseases

Behaviors and Mental Disorders

Lung Neoplasms

Neoplasm Metastasis

Diabetes Mellitus

Brain Neoplasms

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Neoplastic Processes

Central Nervous System Neoplasms

Nervous System Neoplasms

Brain Diseases

Central Nervous System Diseases

Quality of Life

Anti-Inflammatory Agents

Antineoplastic Agents

Antiemetics

Gastrointestinal Agents

All Drugs and Chemicals

Hypoglycemic Agents

Dexamethasone

Metformin

Glucocorticoids

Dexamethasone acetate

Hormones

Hormone Antagonists

Antineoplastic Agents, Hormonal

Patients subjected at a minimum daily dosage of 8 mg through the oral, intramuscular or intravenous administration route (control arm). The total dose can either administered once a day or through a refracted schedule

Patients subjected at a minimum daily dosage of 8 mg through the oral, intramuscular or intravenous administration route.The total dose can either administered once a day or through a refracted schedule.

The same patients subjected at a metformin. Metformin initial dosage will be 850 mg per day, and will be escalated based on patient tolerability up to a maximum of 2550 mg daily (experimental arm).

A minimum daily dosage of 8 mg through the oral, intramuscular or intravenous administration route, once or twice a day.

A minimum daily dosage of Dexamethasone 8 mg through the oral, intramuscular or intravenous administration route, once or twice a day and 2550 mg daily (maximum dose), oral administration (OS) of Metformin; starting dose will be 850 mg/day, to be progressively increased to 1700 mg/day on day 4 and 2550 mg/day on day 7, if well tolerated.

This is a monocentric, open label, randomized Phase II study in patients with brain metastasis from melanoma, lung or breast cancer, who require treatment with high-dose dexamethasone, as defined as a minimum of 8 mg daily based on the clinician judgment, for at least three weeks, with or without radiation therapy. The aim is to investigate the metformin efficacy in preventing the onset of glucocorticoid-induced diabetes and other metabolic perturbations in patients with brain metastases from melanoma, lung or breast cancer.

The study will be conducted in approximately 110 adult patients. aim of the study is to evaluate the effect of oral metformin in preventing GC-induced alterations of systemic metabolism, and in particular GC-induced diabetes. Other clinical objectives of the study consist in investigating the impact of metformin on precocious mortality, deterioration of ECOG PS and local (brain) disease control rate at one month. As an exploratory analysis, the effect of dexamethasone plus/minus metformin on other metabolites or growth factors (including amino acids, fatty acids, ketone bodies, IGF-1), as well as on the number, activation status and metabolism of peripheral blood immune cell populations will be evaluated

Eligible patients will be randomized in a 1:1 ratio. Randomization will be stratified by means of minimization technique according to the following factors: primary tumor (melanoma versus lung versus breast cancer), dexamethasone dosage (8-12 mg vs \>12 mg daily), baseline (pre-enrollment) fasting glycemia (\< 100 versus 100-125 mg/dl). Patients randomized to the experimental arm will discontinue metformin after 30 days, unless diabetes has developed in the meanwhile and the physician believes that metformin is still required for its management. Patients randomized to the control arm who develop steroid-induced diabetes will be prescribed metformin, unless contraindicated, as the preferred therapy option for the management of hyperglycemia. In both treatment arms, dexamethasone will be administered until necessary and at the required dosage in the judgment of the treating physician.

Efficacy of metfOrmin in PrevenTIng Glucocorticoid-induced Diabetes in Patients With Brain Metastases

Efficacy of metfOrmin in PrevenTIng Glucocorticoid-induced Diabetes in Melanoma, breAst or Lung Cancer Patients With Brain Metastases: the Phase II OPTIMAL Study

To evaluate the efficacy of metformin in preventing precocious (14 days) dexamethasone-induced diabetes, as defined as fasting plasma glucose levels ≥ 126 mg/dl, in patients with brain metastases from melanoma, lung or breast cancer.

To study the efficacy of metformin in preventing dexamethasone-induced diabetes at 7 and 30 days after dexamethasone initiation, as defined as fasting plasma glucose levels ≥ 126 mg/dl, in patients with brain metastases from melanoma, lung or breast

To evaluate the efficacy of metformin in modifying short-term mortality (3 months) in patients taking high-dose dexamethasone

To evaluate the efficacy of metformin in modifying the local disease control rate (brain) in patients treated with radiation therapy (RT) plus dexamethasone at 1 month

To test the impact of metformin on precocious modifycation of patient ECOG Performance Status (PS) at 1 month after initiation of dexamethasone therapy.

Patient QoL will be evaluated through the European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ) C-30 version 3.0. The EORTC QLQ.C30 instrument will be scored according to the EORTC guidelines.

To investigate the potential impact of metformin on absolute counts of immune cell populations

To investigate the potential impact of metformin on relative counts and activation status of activated antitumor lymphocytes

To investigate the potential impact of metformin on activated antitumor lymphocytes

To study the effect of metformin in modifying the plasma lipid profile at 14 days after treatment initiation

To study the effect of metformin in modifying the plasma lipid profile at 30 days after treatment initiation

To investigate the effect of metformin on systemic plasma cytokines (G-CSF, GM-CSF, CCL2, VEGFA)

To evaluate the impact of high-dose GCs on gut microbiota populations (30 days)

To evaluate the impact of metformin on gut microbiota populations (30 days)

To study the effect of metformin in modifying the plasma amino acid profile at 14 days after treatment initiation

Fasting Mimicking Diet (or FMD) consists in a 5-day plant-based, low-calorie (600 Kcal on day 1, followed by 300 KCal/day on days 2 to 5), low-protein, low carbohydrate diet

Fasting mimicking diet

Filippo de Braud, M.D.

In preclinical studies, cyclic calorie-restricted diets reduce the risk of several cancers and improve the antitumor activity of standard treatments against already established malignancies.In particular, the fasting mimicking diet (FMD), a plant-based, calorie-restricted, low carbohydrate, low-protein diet to be repeated cyclically every 3-4 weeks, enhances the antitumor activity of cytotoxic chemotherapy, while contemporarily protecting healthy tissues and stimulating antitumor immunity. Most of these effects are likely mediated by the reduction of blood glycemia and growth factors, such as insulin and insulin-like growth factor 1 (IGF-1). When administered to healthy volunteers, cyclic FMD has been shown to be safe and capable of reducing risk factors for different chronic diseases. However, the effects of the FMD in cancer patient populations have not been evaluated so far. This study aims to assess the safety, feasibility and metabolic effects of the FMD in cancer patients treated with different standard antitumor therapies. Patients with any malignancy, with the exception of small cell neuroendocrine tumors, will be considered for enrollment in this study. The FMD will be administered up to a maximum of 8 consecutive cycles in combination with standard adjuvant treatments or therapies for advanced disease.

Tumor and normal cells display differential sensitivity to nutrient and growth factor deprivation. Due to high proliferation rates, most tumor cells depend on continuous energy and metabolic replenishment to renew and duplicate their intracellular components, such as lipid membranes, organelles, DNA and proteins; moreover, as a consequence of constitutive activation of oncogenic pathways, they are unable to halt their proliferation during starvation. This exposes them to acute energetic and anabolic crisis when nutrients (e.g. glucose, amino acids) and growth factors (e.g. insulin) in the extracellular environment are scarce. Starvation-induced toxicity is even higher when tumor cells are exposed to cytotoxic compounds, such as DNA damaging agents. Indeed, repair mechanisms that are essential to survive damage induced by cytotoxic chemotherapy require energy (in the form of ATP units) and metabolic precursors (e.g., nucleotides) that are potentially reduced at the tumor site during nutrient deprivation.

Conversely, cells of healthy tissues are more capable of adapting their proliferation and metabolism to the metabolic contexture. In conditions of nutrient and growth factor deprivation, most normal cells enter a quiescent proliferative status, thus reducing energy- and metabolite-requiring processes, such as DNA, lipid and protein synthesis; they also activate catabolic processes, such as autophagy, which provide the minimal amount of metabolites to survive starvation. Proliferative quiescence not only prevents the occurrence of damage to intracellular structures and orgenelles, but also favors their repair by sparing energy units and essential metabolites.

This differential response to starvation by cancer and normal cells could be potentially exploited to selectively target in vivo human cancers, while sparing healthy tissues. Cyclic fasting or a plant-based, calorie-restricted, low-carbohydrate low-protein diet known as fasting mimicking diet (FMD), are two approaches that have emerged in recent years to selectively target the metabolic vulnerabilities of malignant cells. Indeed, they are capable of inducing meaningful modifications in systemic metabolism, such as reduction of blood glucose insulin and insulin-like growth factor (IGF-1) in both mice and healthy volunteers.

Studies performed in preclinical models of several cancers have demonstrated that cyclic fasting/FMD produce synergistic anticancer effects when combined with cytotoxic chemotherapy, while protecting normal tissues and stimulating antitumor immunity. So far, only a few studies have tested the effects of fasting/FMD in healthy volunteers or cancer patients.

In healthy volunteers, three consecutive cycles of FMD have been shown to be safe and associated with meaningful changes in risk factors for chronic diseases. In cancer patients, a few small studies have demonstrated that short-term fasting (1-3 consecutive days every 3-4 weeks) is feasible and safe in combination with standard chemotherapy, including platinum-based chemotherapy. However, the effects of the FMD in cancer patients have not been investigated so far.

This study,aims to test the safety, feasibility and metabolic effects of the fasting-mimicking diet (FMD) in patients with different malignant neoplasms.

Patients highly motivated to follow the FMD in combination with their standard treatments, will be considered for enrollment in this study. All enrolled patients will be prescribed the same 5-day FMD regimen, which consists of a calorie-restricted (about 600 Kcal on day 1, 300 Kcal/day on days 2 to 5), low-carbohydrate, low-protein diet, which will be repeated every 21-28 days. A maximum of 8 consecutive FMD cycles will be prescribed. During each of the 5 days on FMD, patients will have at least one daily contact (by email or phone) with the study staff to communicate body weight, blood pressure, health conditions, adverse events and the amount of food and beverages introduced (also reported in daily food diaries). In the interval between consecutive FMD cycles, patients will not be prescribed any maintenance diet, but will receive generic dietary recommendations based on World Cancer Research Fund (WCRF 2007) or the American Cancer Society (ACS 2012) recommendations for cancer prevention and cancer survivors.

Patients with any malignancy, except for small cell neuroendocrine tumors, and any disease stage are potentially eligible for this study. Patients with a body mass index (BMI) \< 20 kg/m2, as well as patients who lost more than 5% of their basal weight in the last 3 months, will be excluded from the study. Patients with severe comorbidities, or diabetes mellitus requiring pharmacologic therapies, will be also excluded. The FMD will be permanently discontinued in the case of FMD-related grade 4 adverse events (AEs) or serious adverse events (SAEs), or in the case that patient BMI goes below 20 kg/m2 during the FMD and is not restored between two consecutive FMD cycles.

Patients enrolled in this study will receive standard-of-care treatment for their tumor, including chemotherapy, radiotherapy, molecular target therapy, immunotherapy or best supportive care. Both patients with metastatic disease and patients undergoing adjuvant therapy after curative surgery will be candidate to enter this protocol.

The primary endpoint of the study is safety of the FMD in combination with standard antitumor treatments. Safety will be assessed by reporting and grading FMD-related AEs according to NCI Common Terminology Criteria for Adverse Events (CTCAEs) v 4.03. SAEs will be also reported.

FMD feasibility, FMD-induced metabolic effects, weight changes, and modifications of other blood and biochemical parameters will be secondary endpoints.

Feasibility will be assessed by evaluating the patient ability to comply with the prescribed dietary scheme. To do so, all patients will fill a daily food diary during each of the 5 days on FMD. At the end of the study, diaries will be analyzed. Based on the presence of major and minor deviations from the prescribed dietary scheme, patients will be defined as "compliant" or "not compliant".

FMD-induced metabolic effects will be quantified by measuring blood and urine metabolites and growth factors before the initiation and at completion of each FMD cycle (i.e. before resuming the normal diet). Absolute and relative metabolite and growth factor modifications will be reported. Standard metabolites (e.g. blood glucose, triglycerides, total and HDL cholesterol, urine ketone bodies) will be measured. In selected patients, plasma and whole blood fatty acids and some amino acids will be measured too.

The effect of the FMD on patient weight will be assessed by measuring absolute and relative weight changes during each FMD cycle and along with subsequent cycles.

Changes occurring in other blood parameters, including blood cell counts, aspartate and alanine transaminases, blood urea nitrogen, creatinine and uric acid, C reactive protein, total proteins and albumin, will be also measured before and at the end of each FMD cycle.

Finally, diet-induced changes in peripheral blood fatty acid and phospholipid profiles, as well as of immune cell populations, will be assessed in selected patients as exploratory analyses.

Safety, Feasibility and Metabolic Effects of the Fasting Mimicking Diet (FMD) in Cancer Patients

Safety is assessed by recording each adverse (AE) occurring during the period on diet. All AEs will be graded according to the NCI CTCAE v 4.03. Serious adverse events (SAEs) will be also reported.

Feasibility is defined as the ability of the patient to comply with the prescribed dietary regimen. It will be assessed through the analysis of food diaries filled by patients during the five days of each FMD cycle.

FMD-induced metabolic changes will be evaluated by measuring blood metabolites (glucose, cholesterol, triglycerides) and urinary ketone bodies before and at the completion of each FMD cycle.

FMD-induced changes in blood growth factors will be evaluated by measuring modifications of plasma insulin and serun insulin-like growth factor 1 (IGF-1) concentration before and at the completion of each FMD cycle

Percent changes in body weight will be measured during each FMD cycle and across subsequent FMD cycles.

FMD-induced changes in parameters linked to kidney function, such as blood urea nitrogen, creatinine and uric acid.

FMD-induced changes in parameters linked to liver function, such as aspartate and alanine transaminases, total bilirubin.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Impact of Dietary Intervention on Tumor Immunity: the DigesT Trial	NCT03454282	Breast Cancer Melanoma, Malig...	FMD	18 Years - 75 Years	Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
Efficacy of metfOrmin in PrevenTIng Glucocorticoid-induced Diabetes in Patients With Brain Metastases	NCT04001725	Brain Metastase... Melanoma Lung Cancer Breast Cancer	Dexamethasone Metformin	18 Years - 75 Years	Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
Safety, Feasibility and Metabolic Effects of the Fasting Mimicking Diet (FMD) in Cancer Patients	NCT03340935	Malignant Neopl... Cancer	Fasting mimicki...	18 Years -	Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

Spots Global Cancer Trial Database for metabolic effects