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Metformin Plus/Minus Fasting Mimicking Diet to Target the Metabolic Vulnerabilities of LKB1-inactive Lung Adenocarcinoma (FAME)

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ClinicalTrials.gov Identifier: NCT03709147
Recruitment Status : Not yet recruiting
First Posted : October 17, 2018
Last Update Posted : October 31, 2018
Sponsor:
Information provided by (Responsible Party):
Marina Garassino, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

Brief Summary:
Lung adenocarcinoma with inactive LKB1 has emerged as a particularly aggressive form of lung cancer, with poor response to immune checkpoint inhibitors. Recent preclinical evidences have demonstrated that LKB1-inactive lung adenocarcinoma is characterized by specific metabolic vulnerabilities, which make it hypersensitive to energetic crisis. For instance, by inhibiting mitochondrial metabolism and reducing ATP availability to cancer cells, the antidiabetic compound metformin has anticancer activity and prevents acquired resistance to cisplatin in lung adenocarcinoma with inactive LKB1. Similarly to metformin, glucose starvation, which can be recapitulated in vivo by cyclic fasting or fasting-mimicking diet (FMD), can cause metabolic crisis in these neoplasms. In this trial, the investigators will assess for the first time the efficacy of combining standard-of-care platinum-based chemotherapy with metformin plus/minus FMD in patients with LKB1-inactive, advanced lung adenocarcinoma.

Condition or disease Intervention/treatment Phase
Advanced LKB1-inactive Lung Adenocarcinoma Drug: Metformin Hydrochloride Drug: Cisplatin Drug: Carboplatin Drug: Pemetrexed Dietary Supplement: Fasting-mimicking diet Phase 2

Detailed Description:

Lung cancer is one of the most common malignancies and tumor-related causes of death worldwide. In the last years, significant advances have occurred in the treatment of non small cell lung cancer, in particular for the population of patients with a driver genetic mutation like EGFR, ALK or ROS1. For the remaining cases, the main novelty has been represented by immunotherapy, with anti-PD1/PDL1 agents having demonstrated a benefit over previous standard of care treatments, consisting platinum-based chemotherapy in first line and docetaxel in second line. Nonetheless, not all these patients are amenable to first-line immunotherapy, as only tumors expressing high PD-L1 levels seem to respond to these treatments. Lung adenocarcinoma with LKB1 mutations or macro/micro deletions has a particularly aggressive behavior and seems to be resistant to the effects of immunotherapy. Indeed, such a population appears to be disadvantaged as regards therapeutic options and requires the development of different approaches. LKB1 is involved in intracellular pathways that are crucial in the regulation of cancer cell metabolism. Metabolic reprogramming is a key step in tumorigenesis and several metabolic pathways, including glucose uptake and utilization, or lipid biosynthesis and utilization, are deregulated in cancer cells compared to their normal counterpart. Cells with hypo-active or inactive LKB1 are peculiar in that they show an exquisite vulnerability to energetic deprivation. Indeed, they are unable to survive when exposed to nutrient deprivation or drugs that affect cancer cell bioenergetics or specific metabolic processes. In particular, the class of drugs known as biguanides, which include the antidiabetic compound metformin, are able to inhibit mitochondrial metabolism and to reduce the intracellular concentration of ATP. Based on the well known effects of metformin on cancer cell metabolism, as well as of preclinical evidence that demonstrate a synergism between cisplatin and metformin in lung cancer cell lines and animal models with LKB1 inactivation, the investigators hypothesize that combining standard platinum-based chemotherapy with metformin, with or without a low-calorie, low-carbohydrate, low-protein diet, also known as Fasting Mimicking Diet (FMD), may improve the efficacy of chemotherapy alone for the treatment of patients with LKB1-inactive lung adenocarcinoma.

To test this hypothesis, the investigators will perform an open label, randomized, phase II trial in which patients with advanced LKB1-inactive NSCLC will be randomized in a 1:1 way to receive standard-of-care platinum-pemetrexed chemotherapy plus metformin without (arm A) or with (Arm B) cyclic FMD, The primary study objective is to demonstrate that the experimental treatment (armA plus arm B) improves median PFS from 7.6 months (historical control) to 12 months. Secondary study objectives will be to investigate the impact of the experimental treatment on overall survival, objective response rate, adverse events, systemic metabolic parameters (plasma glucose, amino acids, lipid profile).


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 88 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Single Institution, open-labeled, double arm, non-comparative, randomized, single stage phase II trial, with "pick-the-winner" design.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Exploiting Metformin Plus/Minus Cyclic FAsting Mimicking Diet (FMD) to Improve the Efficacy of Platinum-pemetrexed Chemotherapy in Advanced LKB1-inactive Lung Adenocarcinoma: the FAME Trial
Estimated Study Start Date : October 30, 2018
Estimated Primary Completion Date : September 10, 2023
Estimated Study Completion Date : September 10, 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Arm A
  • cisplatin 75 mg/mq every three weeks OR carboplatin (CBDCA) at an area under the curve (AUC) of 5 every three weeks, up to a maximum of 4 cycles
  • pemetrexed 500 mg/mq every three weeks
  • metformin hydrochloride up to a daily dosage of 1500 mg
Drug: Metformin Hydrochloride
Metformin 1500 mg/day up to disease progression or unacceptable toxicity Every-21-days, 5-day Fasting-mimicking diet (FMD)
Other Name: Metformin

Drug: Cisplatin
Intravenous cisplatin, administered at a dosage of 75 mg/mq every three weeks for a maximim of 4 consecutive cycles
Other Name: CDDP

Drug: Carboplatin
Carboplatin at an area-under-the-curve (AUC) of 5, administered intravenously every-three weeks for a maximum of 4 consecutive cycles
Other Name: CBDCA

Drug: Pemetrexed
Pemetrexed, administered intravenously at the dose of 500 mg/mq every-three weeks up to a maximum of 4 cycles in combination with platinum compounds, and then as a maintenance treatments in patients not undergoing disease progression after the first 4 chemotherapy cycles

Experimental: Arm B
  • cisplatin 75 mg/mq every three weeks OR carboplatin (CBDCA) at an area under the curve (AUC) of 5 every three weeks, up to a maximum of 4 cycles
  • pemetrexed 500 mg/mq every three weeks
  • metformin hydrochloride up to a daily dosage of 1500 mg
  • every-three week, 5-day Fasting-mimicking diet (FMD), up to a maximum of 4 cycles
Drug: Metformin Hydrochloride
Metformin 1500 mg/day up to disease progression or unacceptable toxicity Every-21-days, 5-day Fasting-mimicking diet (FMD)
Other Name: Metformin

Drug: Cisplatin
Intravenous cisplatin, administered at a dosage of 75 mg/mq every three weeks for a maximim of 4 consecutive cycles
Other Name: CDDP

Drug: Carboplatin
Carboplatin at an area-under-the-curve (AUC) of 5, administered intravenously every-three weeks for a maximum of 4 consecutive cycles
Other Name: CBDCA

Drug: Pemetrexed
Pemetrexed, administered intravenously at the dose of 500 mg/mq every-three weeks up to a maximum of 4 cycles in combination with platinum compounds, and then as a maintenance treatments in patients not undergoing disease progression after the first 4 chemotherapy cycles

Dietary Supplement: Fasting-mimicking diet
5-day fasting-mimicking diet regimen, consisting of 700 KCal on day 1, 300 KCal on days 2-4, and 450 KCal on day 5, to be repeated every three weeks up to a maximum of 4 cycles
Other Name: FMD




Primary Outcome Measures :
  1. Progression-free survival [ Time Frame: 60 months ]
    Progression-free survival (PFS), as defined as the time between treatment initiation and disease progression or patient death from any cause, whichever came first


Secondary Outcome Measures :
  1. Grade 3/4 adverse events (AEs) [ Time Frame: 60 months ]
    Incidence (%) Grade 3/4 adverse events (AEs)

  2. Treatment-related adverse events [ Time Frame: 60 months ]
    Incidence (%) of treatment-related adverse events

  3. Patient compliance to the experimental treatment [ Time Frame: 40 months ]
    Patient compliance to the experimental treatment, as evaluated from the analysis of daily food diaries

  4. Objective response rate (ORR) [ Time Frame: 40 months ]
    Objective response rate (ORR), as measured with Radiologic Evaluation Criteria In Solid Tumors (RECIST) version 1.1.

  5. Overall survival (OS) [ Time Frame: 60 months ]
    Overall survival (OS), as defined as the time between treatment initiation and patient death from any cause

  6. Effect of the experimental treatment on plasma glucose levels [ Time Frame: 40 months ]
    Effect of the experimental treatment on plasma glucose levels

  7. Effect of the experimental treatment on serum insulin levels [ Time Frame: 40 months ]
    Effect of the experimental treatment on serum insulin levels

  8. Effect of the experimental treatment on serum IGF-1 levels [ Time Frame: 40 months ]
    Effect of the experimental treatment on serum IGF-1 levels

  9. Effect of the experimental treatment on plasma fatty acids [ Time Frame: 40 months ]
    Effect of the experimental treatment on plasma fatty acids, measured through mass spectrometry analysis

  10. Effect of the experimental treatment on urinary ketones [ Time Frame: 40 months ]
    Effect of the experimental treatment on the concentration of urinary ketones

  11. Impact of plasma glucose modifications on progression free survival [ Time Frame: 40 months ]
    Impact of plasma glucose modifications during the treatment on progression free survival

  12. Impact of serum insulin modifications on progression free survival [ Time Frame: 40 months ]
    Impact of serum insulin modifications during the treatment on progression free survival

  13. Impact of serum IGF-1 modifications on progression free survival [ Time Frame: 40 months ]
    Impact of serum IGF-1 modifications during the treatment on progression free survival

  14. Impact of urinary ketone bodies on progression free survival [ Time Frame: 40 months ]
    Impact of urinary ketone body modifications during the treatment on progression free survival

  15. Impact of lipid profile modifications on progression free survival [ Time Frame: 40 months ]
    Impact of lipid profile modifications during the treatment on progression free survival



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age ≥ 18 and ≤ 75 years.
  • confirmed diagnosis of LKB1-inactive lung adenocarcinoma
  • Absence of EGFR mutations, ALK/ROS1 gene rearrangements and PD-L1 expression < 50% at IHC
  • Presence of advanced disease, as defined as unresectable, locally advanced (stage IIIB) or metastatic disease (stage IV) not candidate to concomitant or sequential definitive radiotherapy on the primary tumor. Palliative radiotherapy on specific disease sites is allowed.
  • Personally signed and dated informed consent document (ICD) indicating that the patient has been informed of all pertinent aspects of the study before enrollment and FMD prescription.
  • Willingness and ability to comply with the FMD protocol, the scheduled visits, treatment plans, laboratory tests and other procedures.
  • Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
  • Patients with brain metastases can be included if they do not cause neurologic symptoms and do not require radiotherapy and corticosteroid dosage higher than 25 mg prednisone equivalent.
  • Presence of adequate bone marrow and organ function as defined by the following laboratory values:

    • ANC ≥ 1.5 x 109/l
    • platelets ≥ 100 x 109/l
    • hemoglobin ≥ 9.0 g/dl
    • calcium (corrected for serum albumin) within normal limits or ≤ grade 1 according to NCI-CTCAE version 4.03 if not clinically significant
    • potassium within the normal limits, or corrected with supplements
    • glomerular filtration rate (GFR) > 60 ml/min as estimated on the basis of 24 h urine collection and analysis, The GFR will be also calculated with the Cockroft-Gault formula on the basis of blood creatinine levels
    • blood uric acid < 10 mg/dl
    • ALT and AST ≤ 2.5 x ULN (Upper Limit of Normal). In the case of documented liver metastases, a threshold of ALT and AST ≤ 5 x ULN will be considered acceptable
    • total bilirubin < 1.5 ULN except for patients with Gilbert syndrome who may only be included in the total bilirubin is < 3.0 x ULN or direct bilirubin < 1.5 x ULN
    • Albumin > 3 g/dL
  • Fasting glucose ≤ 200 mg/dl.
  • Female patients of childbearing potential must agree to sexual abstinence or to use two highly effective method of contraception throughout the study and for at least 30 days after the end of the FMD. Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of the patient. Examples of contraceptive methods with a failure rate of < 1% per year include tubal ligation, male sterilization, hormonal implants, established, proper use of combined oral or injected hormonal contraceptives, and certain intrauterine devices. Alternatively, two methods (e.g., two barrier methods such as a condom and a cervical cap) may be combined to achieve a failure rate of < 1% per year. Barrier methods must always be supplemented with the use of a spermicide. A patient is of childbearing potential if, in the opinion of the Investigator, she is biologically capable of having children and is sexually active. Female patients are not of childbearing potential if they meet at least one of the following criteria:

    • Have undergone a documented hysterectomy and/or bilateral oophorectomy
    • Have medically confirmed ovarian failure
    • Achieved post-menopausal status, defined as: (≥ 12 months of non-therapy-induced amenorrhea) or surgically sterile (absence of ovaries) and have a serum FSH level within the laboratory's reference range for postmenopausal females.

Exclusion Criteria:

  • Prior systemic treatment for advanced lung cancer
  • Having completed (neo)adjuvant platinum-based chemotherapy less than 6 months before disease relapse
  • Diagnosis of a concurrent malignancy in the last 5 years, with the exception of adequately treated, basal or squamous cell carcinoma, non-melanomatous skin cancer or curatively resected cervical cancer. Malignancies diagnosed more than 5 years before the diagnosis of advanced lung adenocarcinomas must have been definitively treated and must have never recurred.
  • Body Mass Index (BMI) < 20 Kg/m2.
  • Anamnesis of alcohol abuse.
  • Unintentional weight loss ≥ 5% in the last three months, unless the patient has a BMI > 25 Kg/m2 at study enrollment. Intentional weight loss is permitted if < 10% in the last three months only if patient BMI is > 22 kg/m2 and weight loss has completely stabilized in the last month.
  • Current status of pregnancy or lactation, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (> 5 mIU/mL).
  • Active HBV or HCV infection.
  • Severe infections within 4 weeks prior to FMD initiation, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia.
  • Active autoimmune diseases that require systemic treatment (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs).
  • History of recent diagnosis of hypothyroidism for which replacement therapy (e.g., thyroxine) and blood endocrine profile (fT3, fT4 and TSH within the normal range) are not stabilized yet.
  • Established diagnosis of diabetes mellitus type I or diabetes mellitus type II that requires pharmacological treatment (including, but not limited to, insulin, insulin secretagogues and metformin).
  • Severe impairment of the gastrointestinal (GI) function or GI disease that may alter the digestion and absorption of nutrients during the re-feeding phase (e.g. active ulcerative diseases of the stomach or intestine, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).
  • Known history of Human Immunodeficiency Virus (HIV) infection.
  • Clinically significant heart disease and/or recent cardiac events including:

    • history of angina pectoris, coronary artery bypass graft (CABG), symptomatic pericarditis, or myocardial infarction within 12 months prior to the start of study treatment;
    • history of documented congestive heart failure (NYHA III-IV);
    • history of cardiac arythmias, (e.g. ventricular tachycardia, chronic atrial fibrillation), complete left bundle branch block, high grade AV block (e.g. bifascicular block, Mobitz type II and third degree AV block), supraventricular, nodal arrhythmias, or conduction abnormality in the previous 12 months.
    • known reduction of left-ventricular ejection fraction (LVEF) to less than 50%, as assessed by multigated radionuclide scintigraphic scan (MUGA) or echocardiography.
  • Previous episodes of symptomatic hypotension causing unconsciousness.
  • Baseline fasting plasma glucose ≤ 65 mg/dl.
  • Ongoing therapy with systemic corticosteroids at a daily dosage equal or superior to 25 mg of prednisone
  • Serious medical or psychiatric illness that in the assessment of the investigator renders the patient not suitable for participation in this clinical study.
  • pO2 < 70 mmHg, lactates above the normal limit and pH values below the normal limit at arterial gas analysis.
  • Requirement of chronic O2 therapy.
  • Other severe heart, liver, pulmonary, kidney comorbidities that are not specified in the inclusion and exclusion criteria, but which could expose the patient to high risk of lactic acidosis.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03709147


Contacts
Layout table for location contacts
Contact: Lital Hollander +39 0239014640 lital.hollander@marionegri.it
Contact: Claudio Vernieri, M.D., Ph.D. +39 0223903066 claudio.vernieri@istitutotumori.mi.it

Locations
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Italy
Marina Chiara Garassino Not yet recruiting
Milan, Italy, 20133
Contact: MARINA CHIARA GARASSINO, MD    0223903813 ext +39    marina.garassino@istitutotumori.mi.it   
Sponsors and Collaborators
Marina Garassino
Investigators
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Principal Investigator: Marina Chiara Garassino, M.D. Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

Publications of Results:
Ding L, Getz G, Wheeler DA, Mardis ER, McLellan MD, Cibulskis K, Sougnez C, Greulich H, Muzny DM, Morgan MB, Fulton L, Fulton RS, Zhang Q, Wendl MC, Lawrence MS, Larson DE, Chen K, Dooling DJ, Sabo A, Hawes AC, Shen H, Jhangiani SN, Lewis LR, Hall O, Zhu Y, Mathew T, Ren Y, Yao J, Scherer SE, Clerc K, Metcalf GA, Ng B, Milosavljevic A, Gonzalez-Garay ML, Osborne JR, Meyer R, Shi X, Tang Y, Koboldt DC, Lin L, Abbott R, Miner TL, Pohl C, Fewell G, Haipek C, Schmidt H, Dunford-Shore BH, Kraja A, Crosby SD, Sawyer CS, Vickery T, Sander S, Robinson J, Winckler W, Baldwin J, Chirieac LR, Dutt A, Fennell T, Hanna M, Johnson BE, Onofrio RC, Thomas RK, Tonon G, Weir BA, Zhao X, Ziaugra L, Zody MC, Giordano T, Orringer MB, Roth JA, Spitz MR, Wistuba II, Ozenberger B, Good PJ, Chang AC, Beer DG, Watson MA, Ladanyi M, Broderick S, Yoshizawa A, Travis WD, Pao W, Province MA, Weinstock GM, Varmus HE, Gabriel SB, Lander ES, Gibbs RA, Meyerson M, Wilson RK. Somatic mutations affect key pathways in lung adenocarcinoma. Nature. 2008 Oct 23;455(7216):1069-75. doi: 10.1038/nature07423.

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Responsible Party: Marina Garassino, Principal Investigator; Head of Unit of Thoracic Oncology, Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
ClinicalTrials.gov Identifier: NCT03709147     History of Changes
Other Study ID Numbers: INT 45/18
First Posted: October 17, 2018    Key Record Dates
Last Update Posted: October 31, 2018
Last Verified: October 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by Marina Garassino, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano:
LKB1-inactive adenocarcinoma
Cisplatin-pemetrexed
Metformin
Fasting-mimicking diet (FMD)
Progression-free survival

Additional relevant MeSH terms:
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Adenocarcinoma
Adenocarcinoma of Lung
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Cisplatin
Carboplatin
Pemetrexed
Metformin
Antineoplastic Agents
Hypoglycemic Agents
Physiological Effects of Drugs
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Folic Acid Antagonists
Nucleic Acid Synthesis Inhibitors