Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

All Conditions

Lung Neoplasms

Carcinoma, Non-Small-Cell Lung

Carcinoma

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

Antineoplastic Agents

All Drugs and Chemicals

Micronutrients

Hematinics

Vitamins

Gemcitabine

Pemetrexed

Cisplatin

Antimetabolites

Enzyme Inhibitors

Folic Acid

Vitamin B Complex

Folic Acid Antagonists

Folinic Acid

Folate

Vitamin B9

Among TS expression positive patients, some will be randomized to Gem/cis therapy

Among patients with TS+, randomised to Pem/cis chemotherapy

Among patients with TS-, some will be randomised to Pem/cis Tx arm

Among patients with TS-, some will be randomised to Gem/Cis Tx arm

Gemcitabine 1000mg/m2 D1, D8 \& cisplatin 70mg/m2 D1 every 3 weeks

Gemcitabine plus cisplatin

Pemetrexed 500mg/m2 \& cisplatin 70mg/m2 D1 every 3 weeks

pemetrexed plus cisplatin

pemetrexed 500mg/m2 \& cisplatin 70mg/m2 every 3 weeks

Myung-Ju Ahn, Pf

Myung-Ju Ahn, M.D., Ph.D.

Jong-Mu Sun, M.D., Ph.D.

This study trys to evaluate the predictive role of thymidylate synthase expression for pemetrexed/cisplatin in Non-small Cell Lung Cancer (NSCLC).

Pemetrexed/Cisplatin Versus Gemcitabine/Cisplatin According to Thymidylate Synthase Expression

A Randomized Phase II Study Comparing Pemetrexed Plus Cisplatin With Gemcitabine Plus Cisplatin According to Thymidylate Synthase Expression in Non-squamous Non-small Cell Lung Cancer

To determine the predictive value of thymidylate synthase expression in NSCLC patients treated with pemetrexed combination therapy by interaction P value

Whether the response rate of CG regimen is higher than that of CP regimen in TS+ patients

Whether the response rate of CP regimen is higher than that of CG regimen in TS- patients

Samsung Medical Center

Rare Diseases

Small Cell Lung Carcinoma

Small Cell Lung Cancer

William Gmeiner, Ph.D, MBA

The purpose of this research study is to determine the amount of a protein named thymidine synthase that is being made by cancer and to develop laboratory models called PDX (patient derived xenografts) to learn more about SCLC (small cell lung cancer) and to begin testing new treatments.

Small cell lung cancer (SCLC) is a highly lethal malignancy that is not treatable with targeted therapies and that does not respond long-term to treatment with cytotoxic chemotherapy1. One distinguishing molecular characteristic of SCLC is very high expression levels of thymidylate synthase (TS). TS plays an important role in de novo nucleotide biosynthesis and the very high TS levels expressed in SCLC cells indicate that these cells require the de novo nucleotide biosynthetic pathway to proliferate. Thus, complete TS inhibition could result in highly favorable outcomes in SCLC patients. TS inhibitors have been evaluated in SCLC clinical trials and have anti-tumoral activity when combined with a second chemotherapeutic agent. However, treatment with TS inhibitors has not been shown to surpass other combination chemotherapy regimens. An important point regarding these clinical studies is that TS activity levels were not monitored as an endpoint of drug response, thus it is not known whether TS activity was efficiently inhibited.Investigators predict that complete TS inhibition will result in favorable outcomes.

With support from Wake Innovations, Investigators are developing a novel fluoropyrimidine polymer, CF10, which strongly inhibits TS. CF10 is a second generation fluoropyrimidine polymer. The first generation polymer, F10, showed excellent anti-cancer activity in animal models of acute myeloid leukemia, glioblastoma, and prostate cancer. CF10 is designed to have improved tumor penetration and better in vivo stability than F10. Investigators hypothesize that CF10 will be highly effective for treating SCLC both as a single agent and in combination with TS inhibitors that target alternative sites of the TS enzyme.

After establishing CF10 has activity as a single agent and in combination with folate-based TS inhibitors (e.g. pemetrexed) in SCLC cell lines and xenograft models, Investigators will test CF10 in patient-derived xenograft (PDX) models and in organoids derived from SCLC patient samples. Investigators will develop PDX models of SCLC and SCLC organoids using transbronchial fine needle aspiration (FNA) from SCLC patients at Baptist/WFBCCC collected by co-I's Bellinger, Dotson, and Thomas. Non-malignant cells will be collected using a brush biopsy to enable comparison of malignant and non-malignant tissue from the same patient with regard to mechanistic endpoints.

DNA will be extracted from the PDX tumor and from the blood sample obtained from the same subject/patient. Both samples will undergo DNA sequencing in the Cancer Genomics Shared Resource. The DNA sequences will be compared to differentiate between tumor-specific mutations and germ-line polymorphisms from the same individual. The mutation profile is characteristic of the tumor and will also be used to test for genetic drift as the PDX tumor is propagated.

TS Overexpression in SCLC: Mechanism and Therapeutic Targeting

TYMS (Thymidylate Synthetase) expression levels will be measured on biopsied malignant tissue as well as non-malignant tissue.

miRNA expression levels will be measured on biopsied malignant tissue as well as non-malignant tissue.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Pemetrexed/Cisplatin Versus Gemcitabine/Cisplatin According to Thymidylate Synthase Expression	NCT01401192	Non-small Cell ...	Gemcitabine plu... pemetrexed plus... pemetrexed plus... Gemcitabine plu...	18 Years -	Samsung Medical Center
TS Overexpression in SCLC: Mechanism and Therapeutic Targeting	NCT03741829	Small Cell Lung...		18 Years -	Wake Forest University Health Sciences
Pemetrexed/Cisplatin Versus Gemcitabine/Cisplatin According to Thymidylate Synthase Expression	NCT01401192	Non-small Cell ...	Gemcitabine plu... pemetrexed plus... pemetrexed plus... Gemcitabine plu...	18 Years -	Samsung Medical Center
TS Overexpression in SCLC: Mechanism and Therapeutic Targeting	NCT03741829	Small Cell Lung...		18 Years -	Wake Forest University Health Sciences
TS Overexpression in SCLC: Mechanism and Therapeutic Targeting	NCT03741829	Small Cell Lung...		18 Years -	Wake Forest University Health Sciences

Spots Global Cancer Trial Database for thymidylate synthase