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BIBW 2992 Plus Simvastatin vs. BIBW 2992 in Previously Treated Patients With Advanced Non-adenocarcinomatous NSCLC

2014-07-23 21:08:33 | BioPortfolio

Summary

The investigators hypothesized that simvastatin may enhance sensitivity to BIBW 2992 in non-adenocarcinoma that is relatively resistant to TKIs. Based on these data, the investigators will research the effectiveness comparing BIBW2992, an irreversible EGFR-TKI, plus simvastatin with BIBW2992 alone in the setting of a randomized phase II study in previously treated patients with advanced non-adenocarcinomatous non-small cell lung cancer (NSCLC).

Description

One of the main reasons of resistance to EGFR tyrosine kinase inhibitors (TKIs) is that there are alternative mechanisms for persistent activating EGFR downstream signaling, including both RAS/Erk and PI3K/Akt kinase pathways. Therefore, simultaneous inhibition of both pathways would be necessary to reduce tumor cell survival more effectively. One of the candidate combinations is concurrent use of EGFR-TKIs and statins, which are irreversible inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase and have been used to treat hypercholesterolemia through blocking the mevalonate biosynthesis pathway. Beside the cholesterol lowering effect, statins have been shown to induce apoptosis in several tumor types. It affects the synthesis of other products of the mevalonate pathway such as isoprenoids, which are used as substrates for prenylation. Attachment of isoprenoids to RAS proteins facilitates their anchoring to the cell membrane where they carried out their roles. By interrupting the biosynthesis of mevalonate, statins inhibit activation of RAS and downstream signaling cascades, including the RAF/MEK/ERK and PI3K/AKT, which play critical roles in regulation of cell survival and proliferation. Therefore, it seems to be a promising therapeutic approach overcoming tumor resistance to EGFR-TKIs, which is associated with RAS activation.

According to the recent clinical result of phase II trial, a randomized phase II study of gefitinib with or without simvastatin in previously treated patients with advanced NSCLC conducted by Han et al.37 gefitinib plus simvastatin combination produced higher response rates than gefitinib alone in patients with non-adenocarcinoma (5/13 [39%] v 1/13 [8%], P=0.06). This finding suggests that simvastatin may enhance sensitivity to gefitinib in non-adenocarcinoma that is relatively resistant to gefitinib. Moreover, by Mantha et al.35 demonstrated that the combination of gefitinib and lovastatin showed significant synergic cytotoxic effects in vitro in a total of 16 squamous cell carcinomas, NSCLC, and colon carcinoma cell lines. Of special interest, these cell lines did not possess the activating mutations of EGFR, which confer increased sensitivity to gefitinib. Nevertheless, combining lovastatin with gefitinib induced more significant inhibition of AKT activation than either agent alone. Additionally, lovastatin significantly enhanced the sensitivity to gefitinib treatment regardless PTEN loss in glioblastoma cell lines. These results suggest that statins can augment EGFR inhibition.

Study Design

Allocation: Randomized, Control: Active Control, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Conditions

Non-small Cell Lung Cancer

Intervention

BIBW 2992, simvastatin

Status

Not yet recruiting

Source

National Cancer Center, Korea

Results (where available)

View Results

Links

Published on BioPortfolio: 2014-07-23T21:08:33-0400

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Trial of BIBW 2992 + Cetuximab in Non-Small Cell Lung Cancer

The primary objective of this trial is to determine the maximum tolerated dose (MTD) and recommended Phase II doses for the combination of BIBW 2992 and cetuximab in patients with non-smal...

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Trial Exploring BIBW 2992 + Paclitaxel (Part A) and BIBW 2992 + Paclitaxel + Bevacizumab (Part B) in Patients With Advanced Solid Tumours

The main purpose of this study is to assess the optimum dose of the following medications when they are given together: - BIBW 2992 and paclitaxel (Taxol) - BIBW 2992 and p...

BIBW 2992 Versus Chemotherapy as First Line Treatment in NSCLC With EGFR Mutation

This randomised, open label phase III trial will be performed in patients with adenocarcinoma of the lung with tumours harbouring an Epidermal Growth Factor Receptor activating mutation. T...

BIBW 2992 and BSC Versus Placebo and BSC in Non-small Cell Lung Cancer Patients Failing Erlotinib or Gefitinib (LUX-LUNG 1)

This randomized, double-blind, multi-center Phase IIb/III trial will be performed in patients with NSCLC who have received previous treatment with at least one but not more than two lines ...

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The usefulness of a recently developed advanced lung cancer inflammation index (ALI) has been reported in advanced non-small-cell lung cancer (NSCLC) and small-cell lung cancer. However, no previous s...

Residential radon and small cell lung cancer. A systematic review.

Residential radon exposure is considered the second cause of lung cancer and the first in never smokers. Nevertheless, the association between the different histological types of lung cancer and radon...

DOES ADVANCED LUNG INFLAMMATION INDEX (ALI) HAVE PROGNOSTIC SIGNIFICANCE IN METASTATIC NON-SMALL CELL LUNG CANCER?

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Medical and Biotech [MESH] Definitions

Malignant neoplasm arising from the epithelium of the BRONCHI. It represents a large group of epithelial lung malignancies which can be divided into two clinical groups: SMALL CELL LUNG CANCER and NON-SMALL-CELL LUNG CARCINOMA.

A form of highly malignant lung cancer that is composed of small ovoid cells (SMALL CELL CARCINOMA).

A heterogeneous aggregate of at least three distinct histological types of lung cancer, including SQUAMOUS CELL CARCINOMA; ADENOCARCINOMA; and LARGE CELL CARCINOMA. They are dealt with collectively because of their shared treatment strategy.

A quinazoline derivative and ANTINEOPLASTIC AGENT that functions as a PROTEIN KINASE INHIBITOR for EGFR associated tyrosine kinase. It is used in the treatment of NON-SMALL CELL LUNG CANCER.

A pharmaceutical preparation of ezetimibe and simvastatin that is used in the treatment of HYPERCHOLESTEROLEMIA and HYPERLIPIDEMIAS.

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