SNPMiner Trials by Shray Alag


SNPMiner Trials: Clinical Trial Report


Report for Clinical Trial NCT03071705

Developed by Shray Alag, 2019.
SNP Clinical Trial Gene

Effect of Metformin in Combination With Tyrosine Kinase Inhibitors (TKI) on Clinical, Biochemical and Nutritional in Patients With Non-Small Cell Lung Carcinoma (NSCLC): Randomized Clinical Trial

Treatment for patients with mutation in the epidermal growth factor receptor (EGFR) with specific domain tyrosine kinase inhibitors (TKIs) has given place to objective clinical response, increase in progression-free survival (PFS) compared to cytotoxic chemotherapy. However, despite clinical success with different TKIs, most patients eventually develop acquired resistance to these agents after an average period of time of 10 months. Recently metformin, an oral hypoglycemic agent, has been associated with reduction in the global risk of incidence and mortality of different types of cancer, by exercising anti-tumor properties. Its role as a chemo-preventive and adjuvant drug in overcoming acquired resistance to chemotherapy, target therapy and immunotherapy in NSCLC is still under discussion. However, preclinical data support the role as an adjuvant drug in the treatment of NSCLC in combination with chemotherapy or EGFR-TKIs. This evidence led to examine the effects of metformin in combination with EGFR-TKIs in a NSCLC cellular line panel, obtaining a different sensibility to the unique use with EGFR-TKIs. The combination of metformin and TKIs reduced the colony forming capacity and proliferation, and induced a huge pro-apoptotic effect in NSCLC cellular lines and resistance in EGFR-TKIs. This suggests that metformin may reduce the resistance to TKIs. A retrospective study in patients from our institution from 2008 to 2014, showed significant clinical benefit in patients who used metformin, improving the global survival. Based on these considerations, we propose a phase II randomized study to assess the effect and safety of metformin in combination with TKIs as second line therapy in patients with NSCLC in advanced stages with EGFR mutation. The main objective of this study is to assess the progression-free survival period in patients with advanced non-small cell lung cancer in treatment with TKIs and metformin versus TKI alone.

NCT03071705 Non-Small Cell Adenocarcinoma Tyrosine Kinase Mutation EGFR Gene Mutation
MeSH: Adenocarcinoma Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

2 Interventions

Name: Metformin

Description: 500 mg PO BID

Type: Drug

Intervention

Name: TKI

Description: standard dose

Type: Drug

Intervention Control


Primary Outcomes

Measure: Overall Survival

Time: Start of treatment until 1-year follow-up

Secondary Outcomes

Description: Inflammatory markers (IL-6, IL-12, TNF-alpha)

Measure: Response Rate

Time: 3 month evaluation after start of treatment

Purpose: Other

Allocation: Randomized

Parallel Assignment


There are 2 SNPs

SNPs


1 L858R

T790M mutation may be present before exposition to TKI and it's generally found with other activating mutations in EGFR (exon 19 deletion and punctual L858R mutation). --- T790M --- --- L858R ---


2 T790M

By PCR it was found that 50% of patients with resistance to TKI develop a specific mutation in exon 20 (T790M). --- T790M ---

T790M mutation may be present before exposition to TKI and it's generally found with other activating mutations in EGFR (exon 19 deletion and punctual L858R mutation). --- T790M ---

A response rate of 8% has been reported in those patients treated with gefitinib or erlotinib whose T790M mutation was positive at the time of the diagnosis, with progression-free survival of 2 months and global survival median of 16 months. --- T790M ---

Despite the advances in treatment have increased response rate and progression-free survival with anti-EGFR TKI in patients with presence of activating mutations, most of them will develop resistance mutations (T790M) and disease progression. --- T790M ---

Acquired resistance will develop in a mean time of 9 to 13 months and the 50% to 60% will be secondary to development of T790M resistance mutation. --- T790M ---

We know that around 50% of cases are caused by an acquired mutation in the EGFR T790M and a lower percentage by MET oncogene amplification, nevertheless, there are other proposed molecular mechanisms, such as the activation of mesenchymal-epithelial transition. --- T790M ---

Finding an effective therapy for patients who develop T790M resistance mutation is required to overcome resistance to first generation anti-EGFR TKI. --- T790M ---

T790M mutation and MET amplification are the main resistance mechanisms to anti-EGFR TKI, other mechanisms such as epithelial-mesenchymal transition (EMT) by TGF-β are resistance mechanisms. --- T790M ---

Pre-clinical studies with cellular lines of lung cancer with anti-EGFR acquired-resistance treatment show that metformin prevents transcription of factors that activate epithelial-mesenchymal transition, inhibiting TGF-β, thus, inhibiting IL-6/JAK1/STAT3 pathway, overcoming anti-EGFR TKI resistance in patients with T790M resistance mutation, in vitro and in vivo. --- T790M ---



HPO Nodes


HPO:
Neoplasm of the lung
Genes 43
WT1 KRAS SLC22A18 STK11 IRF1 AKT1 C11ORF95 PRKN PPP2R1B ERBB2 TRPV3 TSC1 POU6F2 TSC2 EWSR1 RELA KEAP1 REST DIS3L2 SFTPA2 GPC3 MBTPS2 LMNA PTEN BRAF BRCA2 EGFR RB1 TRIP13 PDGFRB TERT SFTPC PIK3CA TRIM28 DICER1 MAP3K8 HPGD SLCO2A1 H19 TP53 NOTCH3 BAP1 WRN
Non-small cell lung carcinoma
Genes 2
TP53 BAP1