Patients with LKB1-mutated advanced lung adenocarcinomas MedDRA version: 21.0 Level: PT Classification code 10025038 Term: Lung adenocarcinoma stage IV System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 21.0 Level: PT Classification code 10025037 Term: Lung adenocarcinoma stage III System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Trade Name: METFORMINA - 500 30 COMPRESSE 500 MG
Product Name: METFORMINA
Product Code: IMP1
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: METFORMINA
Current Sponsor code: IMP1
Concentr
Sponsors
FONDAZIONE IRCCS "ISTITUTO NAZIONALE DEI TUMORI"
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Age included between 18 and 75 years. 2. Histologically confirmed diagnosis of LKB1-mutated lung adenocarcinoma. 3. Absence of EGFR mutations, ALK and ROS-1 rearrangements, high expression of PD-L1 (= 50% in immunoistochemistry). 4. Advanced disease, defined as unresectable, locally advanced (stage IIIB) or metastatic (stage IV), not candidate to concomitant or sequential definitive chemo-radiation. 5. Signed and dated informed consent, indicating that the patient has been informed on all the aspects of the study prior to the enrollment. 6. Patient’s will and capability to respect the protocol recommendations as regards FMD, laboratory tests and other procedures. 7. Eastern Cooperative Oncology Group (ECOG) performance status 0 o 1. 8. In case of presence of brain metastases, absence of neurologic symptoms, need for radiotherapy and steroid therapy at a dose = 25 mg per day of prednisone or analogues. 9. Adequate bone marrow and organ function 10. Fasting plasma glucose concentration = 200 mg/dL. 11. 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 =65 years) yes F.1.3.1 Number of subjects for this age range 28
Exclusion criteria
Exclusion criteria: 1. Previous systemic therapies for advanced lung cancer. 2. Evidence of disease relapse within 6 months from the conclusion of adjuvant or neoadjuvant platinum-based chemotherapy. 3. 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. 4. Body mass index (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 be stable for at least one month. 7. Active pregnancy or breast feeding. 8. Active B or C hepatitis. 9. 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. 10. Active autoimmune diseases requiring systemic treatments (e.g. systemic steroids or immune suppressants). 11. Recent diagnosis of hypothyroidism requiring systemic substitutive hormonal therapy and without stabilization of hormonal profile (fT3, fT4 and TSH within the normal range). 12. Diagnosis of type 1 or 2 diabetes mellitus or requiring pharmacologic therapy (including, but not limited to, insulin, secretagogues and metformin). 13. Serious impair 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). 14. Anamnesis of human immunodeficiency virus (HIV). 15. 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). 16. 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. 17. Reduction in left ventricular ejection fraction to < 50% at the cardiac scan with radionuclides or at echocardiography. 18. Previous episodes of symptomatic hypotension leading to loss of consciousness. 19. Plasma fasting glucose = 65 mg/dL. 20. Active therapy with systemic steroids at a dose = 25 mg per day of prednisone or equivalent. 21. Medical or psychiatric comorbidities rendering the patient not candidate to the clinical trial, according to the investigator’s judgement. 22. pO2 < 70 mmHg, lactates above normal limits and pH value below normal limits at arterial hemogasanalysis. 23. Need for chronic oxygen therapy. 24. 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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To investigate whether the experimental therapy, consisting in platinum plus pemetrexed chemotherapy associated with metformin, alone or combined with cyclicFMD, is capable of improving progression free survival (PFS) in comparison with data from a historical cohort of patients treated with a platinum salt and pemetrexed. If one of the experimental treatments is found to be too toxic, it will be stopped.;Secondary Objective: - To verify the tolerability of each experimental treatment arm and in particular to evaluate the incidence of adverse events (grade 3 and 4). - To evaluate the safety of each treatment arm and in particular the incidence of treatment related adverse events. - To select one of the two experimental treatment arms for further clinical trials, on the basis of its safety and efficacy. - To study the compliance of the treated patients, defined as their capacity of adhere to pharmacologic prescriptions (e.g. metformin) and to the prescribed dietetic regimen. - To estimate the objective tumor response (ORR), detected with radiologic exams and defined according to RECIST version 1.1. - To estimate the patients¿ overall survival (OS) in both experimental treatment arms. - To study the short term (intra-cycle) and long term (inter-cycle) effects of the experimental treatments ;Primary end point(s): Progression-free survival (PFS) ;Timepoint(s) of evaluation of this end point: the time from randomization to objective disease progression, second primary malignancy or death from any cause whichever occurs first | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Objective Response Rate (ORR), ; Overall Survival (OS); Metabolic biomarkers (e.g. plasma glucose, insulin, insulin-like growth factor 1 (IGF-1) levels and whole blood and plasma lipid profile) ; Compliance endpoint: - Dose-intensity, that is the dose of effective drug administrated per unit time (e.g. mg/m2/week) - Percentage of patients with drug dose and/or time modifications - Percentage of patients with experimental dietary regimen modifications - Percentage of premature withdrawals ; Safety endpoint: - Incidence, nature, severity and seriousness of AEs, according of NCI-CTCAE, version 4.0 - Maximum toxicity grade experienced by each patient for each specific toxicity - Percentage of patients experiencing grade 3-4 toxicity for each specific toxicity - Patients with at least a SAE - Patients with at least a serious adverse drug reaction (SADR) - Patients with at least a suspect unexpected serious adverse reaction (SUSAR) ;Timepoint(s) of evaluation of this end point: During 4 chemotherapy cycles and during the follow-up phase (minimum 12 months); time from randomization to death from any cause (maximus 5 years); at baseline and at each chemotherapy cycle (Every three weeks); During treatment; During treatment | — |
Countries
Italy
Contacts
Public ContactUnit¿ Pianificazione e Disegno di s
IRCCS Istituto di Ricerche Farmacologiche Mario Negri
Outcome results
None listed