Clinical Trials /

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

NCT03709147

Description:

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.

Related Conditions:
  • Lung Adenocarcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Metformin Plus/Minus Fasting Mimicking Diet to Target the Metabolic Vulnerabilities of LKB1-inactive Lung Adenocarcinoma
  • 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

Clinical Trial IDs

  • ORG STUDY ID: INT 45/18
  • NCT ID: NCT03709147

Conditions

  • Advanced LKB1-inactive Lung Adenocarcinoma

Interventions

DrugSynonymsArms
Metformin HydrochlorideMetforminArm A
CisplatinCDDPArm A
CarboplatinCBDCAArm A
PemetrexedArm A

Purpose

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.

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).
    

Trial Arms

NameTypeDescriptionInterventions
Arm AExperimentalcisplatin 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
  • Metformin Hydrochloride
  • Cisplatin
  • Carboplatin
  • Pemetrexed
Arm BExperimentalcisplatin 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
  • Metformin Hydrochloride
  • Cisplatin
  • Carboplatin
  • Pemetrexed

Eligibility 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.
      
Maximum Eligible Age:75 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression-free survival
Time Frame:60 months
Safety Issue:
Description: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

Measure:Grade 3/4 adverse events (AEs)
Time Frame:60 months
Safety Issue:
Description:Incidence (%) Grade 3/4 adverse events (AEs)
Measure:Treatment-related adverse events
Time Frame:60 months
Safety Issue:
Description:Incidence (%) of treatment-related adverse events
Measure:Patient compliance to the experimental treatment
Time Frame:40 months
Safety Issue:
Description:Patient compliance to the experimental treatment, as evaluated from the analysis of daily food diaries
Measure:Objective response rate (ORR)
Time Frame:40 months
Safety Issue:
Description:Objective response rate (ORR), as measured with Radiologic Evaluation Criteria In Solid Tumors (RECIST) version 1.1.
Measure:Overall survival (OS)
Time Frame:60 months
Safety Issue:
Description:Overall survival (OS), as defined as the time between treatment initiation and patient death from any cause
Measure:Effect of the experimental treatment on plasma glucose levels
Time Frame:40 months
Safety Issue:
Description:Effect of the experimental treatment on plasma glucose levels
Measure:Effect of the experimental treatment on serum insulin levels
Time Frame:40 months
Safety Issue:
Description:Effect of the experimental treatment on serum insulin levels
Measure:Effect of the experimental treatment on serum IGF-1 levels
Time Frame:40 months
Safety Issue:
Description:Effect of the experimental treatment on serum IGF-1 levels
Measure:Effect of the experimental treatment on plasma fatty acids
Time Frame:40 months
Safety Issue:
Description:Effect of the experimental treatment on plasma fatty acids, measured through mass spectrometry analysis
Measure:Effect of the experimental treatment on urinary ketones
Time Frame:40 months
Safety Issue:
Description:Effect of the experimental treatment on the concentration of urinary ketones
Measure:Impact of plasma glucose modifications on progression free survival
Time Frame:40 months
Safety Issue:
Description:Impact of plasma glucose modifications during the treatment on progression free survival
Measure:Impact of serum insulin modifications on progression free survival
Time Frame:40 months
Safety Issue:
Description:Impact of serum insulin modifications during the treatment on progression free survival
Measure:Impact of serum IGF-1 modifications on progression free survival
Time Frame:40 months
Safety Issue:
Description:Impact of serum IGF-1 modifications during the treatment on progression free survival
Measure:Impact of urinary ketone bodies on progression free survival
Time Frame:40 months
Safety Issue:
Description:Impact of urinary ketone body modifications during the treatment on progression free survival
Measure:Impact of lipid profile modifications on progression free survival
Time Frame:40 months
Safety Issue:
Description:Impact of lipid profile modifications during the treatment on progression free survival

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Marina Garassino

Trial Keywords

  • LKB1-inactive adenocarcinoma
  • Cisplatin-pemetrexed
  • Metformin
  • Fasting-mimicking diet (FMD)
  • Progression-free survival

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