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

NCT03709147 | Unknown Phase 2 DMC

• 1 other identifier: INT 45/18
• Study Type: interventional
• Target: 64
• Locations: 1 country
• Sites: 1

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

Conditions

Advanced LKB1-inactive Lung Adenocarcinoma

Keywords

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

Outcome Measures

Primary Outcomes (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

  60 months

Secondary Outcomes (15)

• Grade 3/4 adverse events (AEs)

  60 months

• Treatment-related adverse events

  60 months

• Patient compliance to the experimental treatment

  40 months

• Objective response rate (ORR)

  40 months

• Overall survival (OS)

  60 months

Study Arms (3)

FAME arm

EXPERIMENTAL

* 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

Drug: Metformin Hydrochloride; Drug: Cisplatin; Drug: Carboplatin; Drug: Pemetrexed; Dietary Supplement: Fasting-mimicking diet; Drug: Pembrolizumab

MERCY arm

EXPERIMENTAL

* 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

Drug: Metformin Hydrochloride; Drug: Cisplatin; Drug: Carboplatin; Drug: Pemetrexed; Drug: Pembrolizumab

BORN arm

NO INTERVENTION

Standard clinical approach.

Interventions

Metformin Hydrochloride DRUG

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

Also known as: Metformin

FAME arm; MERCY arm

Cisplatin DRUG

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

Also known as: CDDP

FAME arm; MERCY arm

Carboplatin DRUG

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

Also known as: CBDCA

FAME arm; MERCY arm

Pemetrexed DRUG

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

FAME arm; MERCY arm

Fasting-mimicking diet DIETARY_SUPPLEMENT

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

Also known as: FMD

FAME arm

Pembrolizumab DRUG

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

FAME arm; MERCY arm

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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;

You may not qualify if:

• 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.
• 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:

Sponsors & Collaborators

• Marina Garassino: lead

Study Sites (1)

Marina Chiara Garassino

Milan, 20133, Italy

RECRUITING

Related Publications (16)

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MeSH Terms

Interventions

Metformin; Cisplatin; Carboplatin; Pemetrexed; pembrolizumab

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals; Chlorine Compounds; Inorganic Chemicals; Nitrogen Compounds; Platinum Compounds; Coordination Complexes; Guanine; Hypoxanthines; Purinones; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Glutamates; Amino Acids, Acidic; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Dicarboxylic

Study Officials

• Marina Chiara Garassino, M.D.

  Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

  PRINCIPAL INVESTIGATOR

Central Study Contacts

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

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator; Head of Unit of Thoracic Oncology, Medical Oncology Department

Model Details: Single Institution, open-labeled, triple arm, non-comparative phase II trial

Study Record Dates

• First Submitted: September 20, 2018
• First Posted: October 17, 2018
• Study Start: October 30, 2018
• Primary Completion: September 10, 2023
• Study Completion: September 10, 2023
• Last Updated: November 16, 2020

Record last verified: 2020-11

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)