AzTrials
AzTrials

Advanced LKB1-inactive Lung AdenocarcinomaPhase 2FAMENCT03709147

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

A Phase 2 study testing Metformin Hydrochloride, Cisplatin and Carboplatin in people with Advanced LKB1-inactive Lung Adenocarcinoma, run by Marina Garassino at 1 site in Italy.

Unknown status

Status not confirmed. The sponsor has not verified this record for over two years, so it may be out of date.

Official record
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Trial 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… Read more about this study

Who is it for?
Ages 18 to 75 years
What is being tested?
Metformin Hydrochloride, Cisplatin and Carboplatin
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
64 participants
Where
1 siteItaly
Study dates
30 Oct 2018to 10 Sep 2023
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 75 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Age included between 18 and 75 years.
  • Histologically confirmed diagnosis of LKB1-inactive lung adenocarcinoma, as defined on the basis of absence of LKB1 expression at immunoistochemistry, and/or presence of pathogenic LKB1 mutations/deletions at next-generation sequencing analysis.
  • Absence of EGFR mutations, ALK and ROS-1 rearrangements, and absence of high expression of PD-L1 (≥ 50% in immunohistochemistry).
  • Advanced disease, defined as unresectable, locally advanced (stage IIIB) or metastatic (stage IV) lung adenocarcinoma, which is not candidate to be treated with concomitant or sequential definitive chemo-radiation.
  • Signed and dated informed consent, indicating that the patient has been informed on all the aspects of the study prior to the enrollment.
  • Patient's will able to respect the protocol recommendations about the FMD regimen, as well as about laboratory tests and other procedures.
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  • Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
  • In case of presence of brain metastases, the patient can be candidated to be enrolled in the study, provided that neurologic symptoms are absent, the patient does not need radiotherapy or treatment with steroids at a dose ≥ 4 mg per day of dexamethasone or analogues.
  • Adequate bone marrow and organ function, defined as follows:
  • absolute neutrophil count ≥ 1.5 x 103/L;
  • platelet count ≥ 100 x 103/L;
  • hemoglobin ≥ 9.0 g/dL;
  • serum albumin-corrected calcium within normal range or with anomalies graded ≤ 1 according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 if not clinically significant;
  • potassium within normal range or corrected with supplements;
  • glomerular filtration rate (GFR) > 60 mL/min, estimated on a 24-hour urine exam and calculated from serum creatinine with Cockroft-Gault formula;
  • uric acid < 10 mg/dL;
  • AST and ALT ≤ 2.5 times upper normal limits, or ≤ 5 times upper normal limits in case of liver metastases;
  • serum bilirubin < 1.5 times upper normal limits, except for patients with Gilbert syndrome who will be considered amenable to be enrolled if total bilirubin is < 3.0 times upper normal limits or direct bilirubin is < 1.5 times upper normal limits;
  • serum albumin > 3 g/dL.
  • Fasting plasma glucose concentration ≤ 200 mg/dL.
  • For women of childbearing potential, consent to maintain abstinence from sexual intercourse or to use highly effective contraceptive methods (that is, with a failure rate < 1% per year) for the whole duration of the study and for almost 30 days after the conclusion of the FMD. Abstinence is acceptable only if in line with the patient's lifestyle. Adequate contraceptive methods include tube ligation, male sterilization, hormone implants, injectable or oral hormone contraceptives and some intra-uterine devices. Alternatively, two different contraceptive methods must be combined (e.g. two barrier methods like condom and cervical cap) in order to obtain a failure rate <1% per year. Barrier methods must always be associated to a sperm killer.
  • Age ≥18 years.
  • Histologically confirmed diagnosis of LKB1-inactive lung adenocarcinoma, as defined on the basis of absence of LKB1 expression at immunoistochemistry, and/or presence of pathogenic LKB1 mutations/deletions at next-generation sequencing analysis.
  • Absence of EGFR mutations, ALK and ROS-1 rearrangements, and absence of high expression of PD-L1 (≥ 50% in immunohistochemistry).
  • Advanced disease, defined as unresectable, locally advanced (stage IIIB) or metastatic (stage IV) lung adenocarcinoma, which is not candidate to be treated with concomitant or sequential definitive chemo-radiation.
  • Signed and dated informed consent, indicating that the patient has been informed on all the aspects of the study prior to the enrollment.
  • Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
  • Adequate bone marrow and organ function, defined as follows:
  • absolute neutrophil count ≥ 1.5 x 103/L;
  • platelet count ≥ 100 x 103/L;- hemoglobin ≥ 9.0 g/dL;
  • serum albumin-corrected calcium within normal range or with anomalies graded ≤ 1 according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 if not clinically significant;
  • potassium within normal range or corrected with supplements;
  • glomerular filtration rate (GFR) > 60 mL/min, estimated on a 24-hour urine exam and calculated from serum creatinine with Cockroft-Gault formula;
  • uric acid < 10 mg/dL;
  • AST and ALT ≤ 2.5 times upper normal limits, or ≤ 5 times upper normal limits in case of liver metastases;
  • serum bilirubin < 1.5 times upper normal limits, except for patients with Gilbert syndrome who will be considered amenable to be enrolled if total bilirubin is < 3.0 times upper normal limits or direct bilirubin is < 1.5 times upper normal limits;
  • serum albumin > 3 g/dL.
  • For women of childbearing potential, consent to maintain abstinence from sexual intercourse or to use highly effective contraceptive methods (that is, with a failure rate < 1% per year) for the whole duration of the study and for almost 30 days after the conclusion of the metformin treatment. Abstinence is acceptable only if in line with the patient's lifestyle. Adequate contraceptive methods include tube ligation, male sterilization, hormone implants, injectable or oral hormone contraceptives and some intra-uterine devices. Alternatively, two different contraceptive methods must be combined (e.g. two barrier methods like condom and cervical cap) in order to obtain a failure rate <1% per year. Barrier methods must always be associated to a sperm killer.
  • Age ≥18 years.
  • Histologically confirmed diagnosis of LKB1-inactive lung adenocarcinoma, as defined on the basis of absence of LKB1 expression at immunoistochemistry, and/or presence of pathogenic LKB1 mutation at next-generation sequencing analysis.
  • Absence of EGFR mutations, ALK and ROS-1 rearrangements, and absence of high expression of PD-L1 (≥ 50% in immunohistochemistry).
  • Advanced disease, defined as unresectable, locally advanced (stage IIIB) or metastatic (stage IV) lung adenocarcinoma, which is not candidate to be treated with concomitant or sequential definitive chemo-radiation.
  • Signed and dated informed consent, indicating that the patient has been informed on all the aspects of the study prior to the enrollment.
  • At least one exclusion criteria of FAME and MERCY arm.

Who cannot join

  • Previous systemic therapies for advanced lung cancer.
  • Evidence of disease relapse within 6 months from the conclusion of adjuvant or neoadjuvant platinum-based chemotherapy.
  • Diagnosis of other malignancies in the previous 5 years, except for adequately treated basal or squamous skin cancer or radically excised cervical cancers. Other malignancies diagnosed more than 5 years before the diagnosis of lung cancer must have been radically treated without evidence of relapse at the time of patient enrollment.
  • Body mass index (BMI) < 20 kg/m2.
  • Anamnesis of alcohol abuse.
  • Non-intentional weight loss ≥ 5% in the previous 3 months, unless the patient has a BMI > 25 kg/ m2 at the time of enrollment in the study, or non-intentional weight loss of ≥ 10% in the previous 3 months, unless the patients has a BMI > 22 kg/m2 at the time of the enrollment in the study. In both cases, weight must have remained stable for at least one month.
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  • Active pregnancy or breast feeding.
  • Active B or C hepatitis.
  • Serious infection in the previous 4 weeks before the start of FMD, including, but not limited to, potential hospitalizations for complications of infections, bacteriemia or serious pneumonitis.
  • Active autoimmune diseases requiring systemic treatments (e.g. systemic steroids or immune suppressants).
  • Recent diagnosis of hypothyroidism requiring systemic substitutive hormonal therapy and without stabilization of hormonal profile (fT3, fT4 and TSH within the normal range).
  • Diagnosis of type 1 or 2 diabetes mellitus requiring pharmacologic therapy (including, but not limited to, insulin, secretagogues and metformin).
  • Serious impairment of gastrointestinal function or gastrointestinal disease potentially altering nutrient digestion or absorption during re-alimentation phase (e.g. active gastric or intestinal ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small intestine resection).
  • Anamnesis of human immunodeficiency virus (HIV).
  • Anamnesis of clinically significant heart disease including:
  • angina pectoris, coronary bypass, symptomatic pericarditis, myocardial infarction in the previous 12 months from the beginning of experimental therapy;
  • congestive heart failure (NYHA III-IV).
  • Anamnesis of cardiac arrhythmias (e.g. ventricular tachycardia, chronic atrial fibrillation, complete bundle branch block, high grade atrio-ventricular block like bi-fascicular block, type II Mobitz and third grade atrio-ventricular block, nodal arrhythmias, supra-ventricular arrhythmias) or conduction abnormalities in the previous 12 months from the beginning of experimental therapy.
  • Reduction in left ventricular ejection fraction to < 50% at the cardiac scan with radionuclides or at echocardiography.
  • Previous episodes of symptomatic hypotension leading to loss of consciousness.
  • Plasma fasting glucose ≤ 65 mg/dL.
  • Active therapy with systemic steroids at a dose ≥ 25 mg per day of prednisone or equivalent for any reason.
  • Medical or psychiatric comorbidities rendering the patient not candidate to the clinical trial, according to the investigator's judgement.
  • pO2 < 60 mmHg, lactates above normal limits and pH value below normal limits at arterial hemogasanalysis.
  • Need for chronic oxygen therapy.
  • Other cardiac, liver, lung or renal comorbidities, not specified in the previous inclusion or exclusion criteria, but potentially exposing the patient to a high risk of lactic acidosis.
  • MERCY arm (chemo-immunotherapy + metformin):
  • Previous systemic therapies for advanced lung cancer.
  • Evidence of disease relapse within 6 months from the conclusion of adjuvant or neoadjuvant platinum-based chemotherapy.
  • Diagnosis of other malignancies in the previous 5 years, except for adequately treated basal or squamous skin cancer or radically excised cervical cancers. Other malignancies diagnosed more than 5 years before the diagnosis of lung cancer must have been radically treated without evidence of relapse.
  • Anamnesis of alcohol abuse.
  • Active pregnancy or breast feeding.
  • Active B or C hepatitis.
  • Serious infection in the previous 4 weeks before the start of metformin treatment, including, but not limited to, potential hospitalizations for complications of infections, bacteriemia or serious pneumonitis.
  • Active autoimmune diseases requiring systemic treatments (e.g. systemic steroids or immune suppressants).
  • Recent diagnosis of hypothyroidism requiring systemic substitutive hormonal therapy and without stabilization of hormonal profile (fT3, fT4 and TSH within the normal range).
  • Diagnosis of type 1 or 2 diabetes mellitus requiring pharmacologic therapy (including, but not limited to, insulin, secretagogues and metformin).
  • Serious impairment of gastrointestinal function or gastrointestinal disease potentially altering nutrient digestion or absorption during re-alimentation phase (e.g. active gastric or intestinal ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small intestine resection).
  • Anamnesis of human immunodeficiency virus (HIV).
  • Anamnesis of clinically significant heart disease including:
  • angina pectoris, coronary bypass, symptomatic pericarditis, myocardial infarction in the previous 12 months from the beginning of experimental therapy;
  • congestive heart failure (NYHA III-IV).
  • Anamnesis of cardiac arrhythmias (e.g. ventricular tachycardia, chronic atrial fibrillation, complete bundle branch block, high grade atrio-ventricular block like bi-fascicular block, type II Mobitz and third grade atrio-ventricular block, nodal arrhythmias, supra-ventricular arrhythmias) or conduction abnormalities in the previous 12 months from the beginning of experimental therapy.
  • Reduction in left ventricular ejection fraction to < 50% at the cardiac scan with radionuclides or at echocardiography.
  • Medical or psychiatric comorbidities rendering the patient not candidate to the clinical trial, according to the investigator's judgement.
  • pO2 < 60 mmHg, lactates above normal limits and pH value below normal limits at arterial hemogasanalysis.
  • Need for chronic oxygen therapy.
  • Other cardiac, liver, lung or renal comorbidities, not specified in the previous inclusion or exclusion criteria, but potentially exposing the patient to a high risk of lactic acidosis.
  • BORN (observational arm):
  • None
  • Patients who are eligible for the FAME arm will be preferentially proposed to be enrolled in the FAME. If they refuse, then they will be proposed to be enrolled in the MERCY arm. If they also refuse to be enrolled in the MERCY arm, they will be proposed to be enrolled in the BORN arm.
  • Patients who are eligible for the MERCY arm will be preferentially proposed to be enrolled in the MERCY arm; if they refuse, the will be proposed to be enrolled in the BORN arm.
  • Finally, patients who are ineligible for both the FAME and MERCY arms will be proposed to be enrolled in the BORN arm.

Trial locations and contacts

1 site in 1 country.

Irene De Simone contact

+39 02 3901 4661

irene.desimone@marionegri.it

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

+39 0223903066

claudio.vernieri@istitutotumori.mi.it

Italy1 site, 1 recruiting

  • Marina Chiara Garassino

    Milan, 20133

    Marina Chiara Garassino, MD, +390223903813 ext. +39, marina.garassino@istitutotumori.mi.it

    Recruiting

Other trials in Italy

About this study

Official title: Exploiting Metformin Plus/Minus Cyclic Fasting Mimicking Diet (FMD) to Improve the Efficacy of First Line Chemo-immunotherapy in Advanced LKB1-inactive Lung Adenocarcinoma

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 chemoimmunotherapy with metformin plus/minus FMD in patients with LKB1-inactive, advanced lung adenocarcinoma.

Read the 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 been observed in the treatment of non small cell lung cancer, in particular for the population of patients with a driver genetic mutation like EGFR and ALK. For the remaining cases, the main novelty has been represented by immunotherapy with anti-PD1/PDL1 agents, which have proved a benefit over previous standard of care (platinum-based chemotherapy in first line and docetaxel in second line). , Only patients wih tumors expressing high PD-L1 levels have had access to immunotherapy alone as first line treatment. For all the remaining cases, the standard-of-care treatment in the first-line setting has remained platinum-based chemotherapy for several years. This algorithm has been recently changed by the approval of combined chemotherapy(platinum salt + pemetrexed) and immunotherapy (pembrolizumab) as a first-line therapy for patients with lung adenocarcinoma and low/absent PD-L1 expression. This regimen has entered into clinical practice following the positive results of a clinical trial, showing superior outcome with the combination than with chemotherapy alone. Lung adenocarcinoma with LKB1 mutations or macro/micro deletions has a particularly aggressive behavior and seems to be resistant to the effects of immunotherapy, either alone or in combination with chemotherapy. Indeed, such a population appears to be disadvantaged as regards therapeutic options and requires the development of different approaches. LKB1 enzyme 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, and have shown antitumor activity in mouse xenografts of LKB1-mutated lung adenocarcinomas. Based on the well known effects of metformin on cancer cell metabolism, as well as on preclinical evidence showing synergistic activity of cisplatin and metformin in lung cancer cell lines and animal models with LKB1 deletion, we hypothesize that combining chemoimmunotherapy (platinum salt + pemetrexed + pembrolizumab) with either metformin (MERCY arm), or metformin plus a lowcalorie, low-carbohydrate, low-protein diet also known as Fasting Mimicking Diet (FMD) (FAME arm), may improve the efficacy of standard treatment alone for patients with LKB1-inactive lung adenocarcinoma.

The patients considered eligible and enrolled in the study will be included in FAME, MERCY or BORN arms according to the aforementioned eligibility criteria. Patients in each arm will receive the following treatment:

  • FAME -> up to a maximum of 4 cycles of a platinum salt + pemetrexed + pembrolizumab in association to metformin and to tri-weekly, 5 day-long cycles of FMD.
  • MERCY -> up to a maximum of 4 cycles of a platinum salt + pemetrexed + pembrolizumab in association to metformin.
  • BORN -> standard treatment at investigator's choice or observation only in case of clinical conditions contraindicating any active therapy.

In both arms FAME and MERCY, the patients with stable or responding disease after 4 cycles of chemotherapy will continue with maintenance pemetrexed and pembrolizumab in association to metformin until disease progression and/or inacceptable toxicity.

Being tested
Metformin Hydrochloride, Cisplatin, Carboplatin, Pemetrexed, Fasting-mimicking diet
Keywords
LKB1-inactive adenocarcinoma, Cisplatin-pemetrexed, Metformin, Fasting-mimicking diet (FMD), Progression-free survival

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Metformin HydrochlorideDrug

    Also called Metformin

    Metformin 1500 mg/day up to disease progression or unacceptable toxicity Every-21-days, 5-day Fasting-mimicking diet (FMD)

  • CisplatinDrug

    Also called CDDP

    Intravenous cisplatin, administered at a dosage of 75 mg/mq every three weeks for a maximim of 4 consecutive cycles

  • CarboplatinDrug

    Also called CBDCA

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

  • PemetrexedDrug

    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

  • Fasting-mimicking dietDietary supplement

    Also called FMD

    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

  • PembrolizumabDrug

    Pembrolizumab, administered intravenously at the flat dose of 200 mg 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

Study groups in NCT03709147
Study groupRoleWhat they receive
FAME armExperimental* 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 * pembrolizumab 200 mg flat dose 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
Receives: Drug: Metformin Hydrochloride; Drug: Cisplatin; Drug: Carboplatin; Drug: Pemetrexed; Dietary Supplement: Fasting-mimicking diet; Drug: Pembrolizumab
MERCY armExperimental* 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 * pembrolizumab 200 mg flat dose every three weeks * metformin hydrochloride up to a daily dosage of 1500 mg
Receives: Drug: Metformin Hydrochloride; Drug: Cisplatin; Drug: Carboplatin; Drug: Pemetrexed; Drug: Pembrolizumab
BORN armNo interventionStandard clinical approach.

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Progression-free survival

    Progression-free survival (PFS), as defined as the time between treatment initiation and disease progression or patient death from any cause, whichever came first

    Measured: 60 months

Secondary outcomes (15)

  1. Grade 3/4 adverse events (AEs)

    Incidence (%) Grade 3/4 adverse events (AEs)

    Measured: 60 months

  2. Treatment-related adverse events

    Incidence (%) of treatment-related adverse events

    Measured: 60 months

  3. Patient compliance to the experimental treatment

    Patient compliance to the experimental treatment, as evaluated from the analysis of daily food diaries

    Measured: 40 months

  4. Objective response rate (ORR)

    Objective response rate (ORR), as measured with Radiologic Evaluation Criteria In Solid Tumors (RECIST) version 1.1.

    Measured: 40 months

  5. Overall survival (OS)

    Overall survival (OS), as defined as the time between treatment initiation and patient death from any cause

    Measured: 60 months

  6. Effect of the experimental treatment on plasma glucose levels

    Effect of the experimental treatment on plasma glucose levels

    Measured: 40 months

  7. Effect of the experimental treatment on serum insulin levels

    Effect of the experimental treatment on serum insulin levels

    Measured: 40 months

  8. Effect of the experimental treatment on serum IGF-1 levels

    Effect of the experimental treatment on serum IGF-1 levels

    Measured: 40 months

  9. Effect of the experimental treatment on plasma fatty acids

    Effect of the experimental treatment on plasma fatty acids, measured through mass spectrometry analysis

    Measured: 40 months

  10. Effect of the experimental treatment on urinary ketones

    Effect of the experimental treatment on the concentration of urinary ketones

    Measured: 40 months

  11. Impact of plasma glucose modifications on progression free survival

    Impact of plasma glucose modifications during the treatment on progression free survival

    Measured: 40 months

  12. Impact of serum insulin modifications on progression free survival

    Impact of serum insulin modifications during the treatment on progression free survival

    Measured: 40 months

  13. Impact of serum IGF-1 modifications on progression free survival

    Impact of serum IGF-1 modifications during the treatment on progression free survival

    Measured: 40 months

  14. Impact of urinary ketone bodies on progression free survival

    Impact of urinary ketone body modifications during the treatment on progression free survival

    Measured: 40 months

  15. Impact of lipid profile modifications on progression free survival

    Impact of lipid profile modifications during the treatment on progression free survival

    Measured: 40 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted17 Oct 2018
  2. Study start30 Oct 2018
  3. Primary completion10 Sep 2023 (estimated)
  4. Study completion10 Sep 2023 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Parallel groups
Model description
Single Institution, open-labeled, triple arm, non-comparative phase II trial
Masking
None (open label)
Enrolment
64 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03709147
Sponsor's protocol ID
INT 45/18
Acronym
FAME
Status last verified
Nov 2020
First submitted
20 Sep 2018
Last updated
16 Nov 2020
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • 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.

    PubMed 18948947

  • Chen Z, Fillmore CM, Hammerman PS, Kim CF, Wong KK. Non-small-cell lung cancers: a heterogeneous set of diseases. Nat Rev Cancer. 2014 Aug;14(8):535-46. doi: 10.1038/nrc3775.

    PubMed 25056707

  • McCleland ML, Adler AS, Deming L, Cosino E, Lee L, Blackwood EM, Solon M, Tao J, Li L, Shames D, Jackson E, Forrest WF, Firestein R. Lactate dehydrogenase B is required for the growth of KRAS-dependent lung adenocarcinomas. Clin Cancer Res. 2013 Feb 15;19(4):773-84. doi: 10.1158/1078-0432.CCR-12-2638. Epub 2012 Dec 6.

    PubMed 23224736

  • Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011 Mar 4;144(5):646-74. doi: 10.1016/j.cell.2011.02.013.

    PubMed 21376230

  • Vernieri C, Casola S, Foiani M, Pietrantonio F, de Braud F, Longo V. Targeting Cancer Metabolism: Dietary and Pharmacologic Interventions. Cancer Discov. 2016 Dec;6(12):1315-1333. doi: 10.1158/2159-8290.CD-16-0615. Epub 2016 Nov 21.

    PubMed 27872127

  • Shaw RJ, Bardeesy N, Manning BD, Lopez L, Kosmatka M, DePinho RA, Cantley LC. The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell. 2004 Jul;6(1):91-9. doi: 10.1016/j.ccr.2004.06.007.

    PubMed 15261145

  • Shaw RJ, Kosmatka M, Bardeesy N, Hurley RL, Witters LA, DePinho RA, Cantley LC. The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. Proc Natl Acad Sci U S A. 2004 Mar 9;101(10):3329-35. doi: 10.1073/pnas.0308061100. Epub 2004 Feb 25.

    PubMed 14985505

  • Shackelford DB, Shaw RJ. The LKB1-AMPK pathway: metabolism and growth control in tumour suppression. Nat Rev Cancer. 2009 Aug;9(8):563-75. doi: 10.1038/nrc2676.

    PubMed 19629071

  • Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N, Musi N, Hirshman MF, Goodyear LJ, Moller DE. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001 Oct;108(8):1167-74. doi: 10.1172/JCI13505.

    PubMed 11602624

  • Shackelford DB, Abt E, Gerken L, Vasquez DS, Seki A, Leblanc M, Wei L, Fishbein MC, Czernin J, Mischel PS, Shaw RJ. LKB1 inactivation dictates therapeutic response of non-small cell lung cancer to the metabolism drug phenformin. Cancer Cell. 2013 Feb 11;23(2):143-58. doi: 10.1016/j.ccr.2012.12.008. Epub 2013 Jan 24.

    PubMed 23352126

  • Lee C, Raffaghello L, Brandhorst S, Safdie FM, Bianchi G, Martin-Montalvo A, Pistoia V, Wei M, Hwang S, Merlino A, Emionite L, de Cabo R, Longo VD. Fasting cycles retard growth of tumors and sensitize a range of cancer cell types to chemotherapy. Sci Transl Med. 2012 Mar 7;4(124):124ra27. doi: 10.1126/scitranslmed.3003293. Epub 2012 Feb 8.

    PubMed 22323820

  • Safdie FM, Dorff T, Quinn D, Fontana L, Wei M, Lee C, Cohen P, Longo VD. Fasting and cancer treatment in humans: A case series report. Aging (Albany NY). 2009 Dec 31;1(12):988-1007. doi: 10.18632/aging.100114.

    PubMed 20157582

  • de Groot S, Vreeswijk MP, Welters MJ, Gravesteijn G, Boei JJ, Jochems A, Houtsma D, Putter H, van der Hoeven JJ, Nortier JW, Pijl H, Kroep JR. The effects of short-term fasting on tolerance to (neo) adjuvant chemotherapy in HER2-negative breast cancer patients: a randomized pilot study. BMC Cancer. 2015 Oct 5;15:652. doi: 10.1186/s12885-015-1663-5.

    PubMed 26438237

  • Dorff TB, Groshen S, Garcia A, Shah M, Tsao-Wei D, Pham H, Cheng CW, Brandhorst S, Cohen P, Wei M, Longo V, Quinn DI. Safety and feasibility of fasting in combination with platinum-based chemotherapy. BMC Cancer. 2016 Jun 10;16:360. doi: 10.1186/s12885-016-2370-6.

    PubMed 27282289

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Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Metformin Hydrochloride, Cisplatin and Carboplatin in people with Advanced LKB1-inactive Lung Adenocarcinoma, run by Marina Garassino at 1 site in Italy.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 44 inclusion and 53 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: status not confirmed, as of the sponsor's last update on 16 Nov 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

Contact Irene De Simone (+39 02 3901 4661, irene.desimone@marionegri.it), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Progression-free survival (time frame: 60 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03709147, which also lists 16 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 16 Nov 2020; AzTrials last refreshed its copy on 7 Nov 2026.

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