Anticancer Activity of Nicotinamide on Lung Cancer

Study Overview
=================
Brief Summary
-----------------
Nicotinamide is an inhibitor of human sirtuins (HDAC III), and is found to re-activate epigenetically silenced tumor suppressors, RUNX3 (runt-related gene 3) and others, in cancer cells. Nicotinamide was found to be effective in several animal cancer models including lung, bladder, liver, etc. The purpose of this study is to determine whether nicotinamide is also effective in the treatment of human lung cancer.

Detailed Description
-----------------
The standard therapy to the EGFR (epidermal growth factor receptor) mutation positive non-small-cell lung cancer patients who are not eligible to operation is to administer EGFR-TKIs (tyrosine kinase inhibitors, gefitinib or erlotinib). To determine the effectiveness of nicotinamide on lung cancer, nicotinamide or placebo tablet will be co-administered with gefitinib or erlotinib for two years until the event or censoring occurs. The stratified block randomization was designed with 3 covariates (EGFR mutation status, kind of EGFR-TKI, ECOG (Eastern Cooperative Oncology Group) performance status score variation). The size of lesions will be checked every other months by radiology. PD (progressive disease) will be assessed according to RECIST(Response Evaluation Criteria in Solid Tumors)1.1. After observing 36 events, an interim analysis of hazard ratio by Cox proportional hazard regression will be performed. The final analysis will be done by the same protocol after observation of 72 events. The significance level of the interim and final analysis were set to 0.0075 and 0.0209 respectively. Response rate, quality of life (measured by 10 questions at every visit), and overall survival will be analysed together. All other adverse reactions will be analysed and reported, if there.

Official Title
-----------------
Randomized Double-blinded Comparative Trial to Study the Add-on Activity of Combination Treatment of Nicotinamide on Progression Free Survival for EGFR Mutated Lung Cancer Terminal Stage Patients Being Treated With Gefitinib or Erlotinib

Conditions
-----------------
Non-Small-Cell Lung Carcinoma

Intervention / Treatment
-----------------
* Drug: Nicotinamide


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Operation-impossible stage 4 non-small-cell lung carcinoma (NSCLC), or recurred terminal stage NSCLC after previous operation or radiation therapy EGFR mutated (exon 19 deletion or L858R mutation) Life expectation more than 3 months More than 1 measurable lesions by RECIST 1.1 which were not exposed to radiation previously ECOG (Eastern Cooperative Oncology Group ) performance status grade 0 2 Who signed the informed consent form Exclusion Criteria: Who had received chemotherapy or EGFR tyrosin kinase inhibitors previously, except whom had received operation at least 6 months ago and received supplementary chemotherapy Who has metastasized brain lesion that needs operation or radiation therapy Above grade 2, CTCAE (Common Toxicity Criteria for Adverse Effects) 4.0 criteria for blood, liver and kidney Who does Not agree to contraception Who has allergy to nicotinamide

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nicotinamide<br>Nicotinamide with EGFR-TKI: gefitinib (250mg tab) or erlotinib (150mg tab) - per oral, once a day nicotinamide (500mg tab) - per oral, twice a day, until the event or censoring occurs | Drug: Nicotinamide<br>* Nicotinamide (1g/day) or placebo treatment is added to the standard drug treatment (gefitinib or erlotinib) to EGFR mutated NSCLC patients<br>* Other names: Amina-X;|
| Placebo Comparator: Placebo<br>Placebo tablet with EGFR-TKI: gefitinib (250mg tab) or erlotinib (150mg tab) - per oral, once a day placebo tablet - per oral, twice a day, until the event or censoring occurs | Drug: Nicotinamide<br>* Nicotinamide (1g/day) or placebo treatment is added to the standard drug treatment (gefitinib or erlotinib) to EGFR mutated NSCLC patients<br>* Other names: Amina-X;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hazard ratio (PFS) of the nicotinamide arm to the placebo arm | Cox regression analysis | two year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate | chi-square test of complete response and partial response (RECIST 1.1) | two year | 
| Difference in quality of life between the nicotinamide arm and the placebo arm | measured by the cancer-related QOL questionaire response (questioned at each visit) | two year | 
| Overall survival | Cox regression analysis | two year | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
EGFR mutated lung cancer