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Report for Clinical Trial NCT02151721

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

Phase I of Vorinostat-Iressa Combined Therapy on Resistance by BIM Polymorphysim in EGFR Mutant Lung Cancer

- Gefitinib is an orally active epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI). However, 20-30% of patients with EGFR-activating mutations show intrinsic resistance to EGFR-TKI. - EGFR-mutant non-small cell lung cancer (NSCLC) cells with BIM (BCL2L11) deletion polymorphism show the impaired generation of BIM with the proapoptotic BH3 domain, as well as resistance to EGFR-TKI-induced apoptosis. - Both BIM polymorphism (12.9%) and EGFR mutations (50% in lung adenocarcinoma) are more prevalent in the East Asian than in Caucasian populations. BIM is a BH3-only proapoptotic member of the Bcl-2 protein family. BIM upregulation is required for apoptosis induction by EGFR-TKI in EGFR-mutant NSCLC. - Vorinostat (suberoylanilide hydroxamic acid [SAHA]) is a small-molecule inhibitor of histone deacetylase (HDAC) and induces cell differentiation, cell cycle arrest, and apoptosis in several tumor cells. HDAC inhibition can epigenetically restore BIM function and death sensitivity of EGFR-TKI in patients with EGFR-mutant NSCLC in whom resistance to EGFR-TKI is associated with a common BIM polymorphism. EGFR-TKI resistance due to the BIM polymorphism may be able to be circumvented in combination with HDAC inhibition of vorinostat with gefitinib in NSCLC.

NCT02151721 Non-Small-Cell Lung Carcinoma
MeSH: Carcinoma, Non-Small-Cell Lung
HPO: Non-small cell lung carcinoma

1 Interventions

Name: Vorinostat, gefitinib

Description: Vorinostat 200, 300, or 400 mg orally once daily on days 1-7 with washout on days 8-14 plus gefitinib 250 mg orally once daily on days 1-14

Type: Drug

vorinostat, gefitinib, combination


Primary Outcomes

Description: MTD (Maximum Tolerated Dose)defined as the highest dose level at which < 2 out of 6 patients experienced a DLT.

Measure: MTD (Maximum Tolerated Dose)

Time: Second cycle (Day 28)

Purpose: Treatment

Single Group Assignment


There are 2 SNPs

SNPs


1 L858R

MTD (Maximum Tolerated Dose)defined as the highest dose level at which < 2 out of 6 patients experienced a DLT.. Inclusion Criteria: - Histologically or cytologically diagnosed NSCLC (excluding squamous cell carcinoma) - NSCLC of clinicopathologic stage IIIB or IV for which radical radiation therapy is impracticable, or recurrence after surgery - EGFR mutations (deletion of exon 19 and L858R mutation of exon 21) for which the clinical benefits of an EGFR-TKI (gefitinib or erlotinib) are recognized by testing methods that are listed by the national health insurance - Having a history of treatment with an EGFR-TKI (gefitinib or erlotinib) and a history of pathology deterioration during treatment - Having a history of treatment with cytotoxic anticancer agents (not including pre- or postoperative chemotherapy that has passed 1 or more year from the day of final administration) - Confirmed BIM polymorphism by the PCR fragment analytical method and the sequence method at the central laboratory - Having a lesion measureable according to the RECIST guidelines revised version 1.1 (20 mm or larger in 10-mm slice CT, 10 mm or larger in 5-mm slice CT, 15 mm or larger in the minor axis of a lymph node). --- L858R ---

- Verified HBs antigen positivity or HCV antibody positivity (excluding the case of confirmed HCV-RNA negativity) Inclusion Criteria: - Histologically or cytologically diagnosed NSCLC (excluding squamous cell carcinoma) - NSCLC of clinicopathologic stage IIIB or IV for which radical radiation therapy is impracticable, or recurrence after surgery - EGFR mutations (deletion of exon 19 and L858R mutation of exon 21) for which the clinical benefits of an EGFR-TKI (gefitinib or erlotinib) are recognized by testing methods that are listed by the national health insurance - Having a history of treatment with an EGFR-TKI (gefitinib or erlotinib) and a history of pathology deterioration during treatment - Having a history of treatment with cytotoxic anticancer agents (not including pre- or postoperative chemotherapy that has passed 1 or more year from the day of final administration) - Confirmed BIM polymorphism by the PCR fragment analytical method and the sequence method at the central laboratory - Having a lesion measureable according to the RECIST guidelines revised version 1.1 (20 mm or larger in 10-mm slice CT, 10 mm or larger in 5-mm slice CT, 15 mm or larger in the minor axis of a lymph node). --- L858R ---


2 T790M

- Having a large volume of or uncontrollable pleural effusion, ascites, or pericardial effusion - Detection of known EGFR-TKI resistance acquired by mutations of the genes, e.g., T790M. --- T790M ---



HPO Nodes


HPO:
Non-small cell lung carcinoma
Genes 3
TP53 TP53 BAP1