Metformin Plus/Minus Fasting Mimicking Diet to Target the Metabolic Vulnerabilities of LKB1-inactive Lung Adenocarcinoma
- Conditions
- Advanced LKB1-inactive Lung Adenocarcinoma
- Interventions
- Dietary Supplement: Fasting-mimicking diet
- Registration Number
- NCT03709147
- Lead Sponsor
- Marina Garassino
- 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.
- 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.
Recruitment & Eligibility
- Status
- UNKNOWN
- Sex
- All
- Target Recruitment
- 64
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description FAME arm Fasting-mimicking diet * 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 FAME arm Metformin Hydrochloride * 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 FAME arm Cisplatin * 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 FAME arm Carboplatin * 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 FAME arm Pemetrexed * 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 FAME arm Pembrolizumab * 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 MERCY arm Metformin Hydrochloride * 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 MERCY arm Carboplatin * 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 MERCY arm Cisplatin * 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 MERCY arm Pemetrexed * 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 MERCY arm Pembrolizumab * 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
- Primary Outcome Measures
Name Time Method Progression-free survival 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
Name Time Method Treatment-related adverse events 60 months Incidence (%) of treatment-related adverse events
Overall survival (OS) 60 months Overall survival (OS), as defined as the time between treatment initiation and patient death from any cause
Effect of the experimental treatment on serum IGF-1 levels 40 months Effect of the experimental treatment on serum IGF-1 levels
Effect of the experimental treatment on plasma fatty acids 40 months Effect of the experimental treatment on plasma fatty acids, measured through mass spectrometry analysis
Impact of serum IGF-1 modifications on progression free survival 40 months Impact of serum IGF-1 modifications during the treatment on progression free survival
Patient compliance to the experimental treatment 40 months Patient compliance to the experimental treatment, as evaluated from the analysis of daily food diaries
Effect of the experimental treatment on serum insulin levels 40 months Effect of the experimental treatment on serum insulin levels
Impact of serum insulin modifications on progression free survival 40 months Impact of serum insulin modifications during the treatment on progression free survival
Impact of urinary ketone bodies on progression free survival 40 months Impact of urinary ketone body modifications during the treatment on progression free survival
Grade 3/4 adverse events (AEs) 60 months Incidence (%) Grade 3/4 adverse events (AEs)
Objective response rate (ORR) 40 months Objective response rate (ORR), as measured with Radiologic Evaluation Criteria In Solid Tumors (RECIST) version 1.1.
Effect of the experimental treatment on plasma glucose levels 40 months Effect of the experimental treatment on plasma glucose levels
Effect of the experimental treatment on urinary ketones 40 months Effect of the experimental treatment on the concentration of urinary ketones
Impact of plasma glucose modifications on progression free survival 40 months Impact of plasma glucose modifications during the treatment on progression free survival
Impact of lipid profile modifications on progression free survival 40 months Impact of lipid profile modifications during the treatment on progression free survival
Trial Locations
- Locations (1)
Marina Chiara Garassino
🇮🇹Milan, Italy