Anticancer Activity of Nicotinamide on Lung Cancer

NCT ID: NCT02416739

Last Updated: 2020-01-27

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

UNKNOWN

Clinical Phase

PHASE2/PHASE3

Total Enrollment

110 participants

Study Classification

INTERVENTIONAL

Study Start Date

2015-03-31

Study Completion Date

2020-06-30

Brief Summary

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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

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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.

Conditions

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Non-Small-Cell Lung Carcinoma

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

TRIPLE

Participants Caregivers Investigators

Study Groups

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Nicotinamide

Nicotinamide with EGFR-TKI:

1. gefitinib (250mg tab) or erlotinib (150mg tab) - per oral, once a day
2. nicotinamide (500mg tab) - per oral, twice a day, until the event or censoring occurs

Group Type EXPERIMENTAL

Nicotinamide

Intervention Type DRUG

Nicotinamide (1g/day) or placebo treatment is added to the standard drug treatment (gefitinib or erlotinib) to EGFR mutated NSCLC patients

Placebo

Placebo tablet with EGFR-TKI:

1. gefitinib (250mg tab) or erlotinib (150mg tab) - per oral, once a day
2. placebo tablet - per oral, twice a day, until the event or censoring occurs

Group Type PLACEBO_COMPARATOR

Nicotinamide

Intervention Type DRUG

Nicotinamide (1g/day) or placebo treatment is added to the standard drug treatment (gefitinib or erlotinib) to EGFR mutated NSCLC patients

Interventions

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Nicotinamide

Nicotinamide (1g/day) or placebo treatment is added to the standard drug treatment (gefitinib or erlotinib) to EGFR mutated NSCLC patients

Intervention Type DRUG

Other Intervention Names

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Amina-X

Eligibility Criteria

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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
Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Il Yeong Park, Ph.D.

OTHER

Sponsor Role lead

Responsible Party

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Il Yeong Park, Ph.D.

Professor

Responsibility Role SPONSOR_INVESTIGATOR

Principal Investigators

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Il Yeong Park, PhD

Role: STUDY_DIRECTOR

Chungbuk National University

Locations

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Chonnam National University Hwasun Hospital

Hwasun, Chonnam, South Korea

Site Status

Countries

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South Korea

References

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Li QL, Kim HR, Kim WJ, Choi JK, Lee YH, Kim HM, Li LS, Kim H, Chang J, Ito Y, Youl Lee K, Bae SC. Transcriptional silencing of the RUNX3 gene by CpG hypermethylation is associated with lung cancer. Biochem Biophys Res Commun. 2004 Jan 30;314(1):223-8. doi: 10.1016/j.bbrc.2003.12.079.

Reference Type BACKGROUND
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Li QL, Ito K, Sakakura C, Fukamachi H, Inoue Ki, Chi XZ, Lee KY, Nomura S, Lee CW, Han SB, Kim HM, Kim WJ, Yamamoto H, Yamashita N, Yano T, Ikeda T, Itohara S, Inazawa J, Abe T, Hagiwara A, Yamagishi H, Ooe A, Kaneda A, Sugimura T, Ushijima T, Bae SC, Ito Y. Causal relationship between the loss of RUNX3 expression and gastric cancer. Cell. 2002 Apr 5;109(1):113-24. doi: 10.1016/s0092-8674(02)00690-6.

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Avalos JL, Bever KM, Wolberger C. Mechanism of sirtuin inhibition by nicotinamide: altering the NAD(+) cosubstrate specificity of a Sir2 enzyme. Mol Cell. 2005 Mar 18;17(6):855-68. doi: 10.1016/j.molcel.2005.02.022.

Reference Type BACKGROUND
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Black JC, Mosley A, Kitada T, Washburn M, Carey M. The SIRT2 deacetylase regulates autoacetylation of p300. Mol Cell. 2008 Nov 7;32(3):449-55. doi: 10.1016/j.molcel.2008.09.018.

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Omar MF, Ito K, Nga ME, Soo R, Peh BK, Ismail TM, Thakkar B, Soong R, Ito Y, Salto-Tellez M. RUNX3 downregulation in human lung adenocarcinoma is independent of p53, EGFR or KRAS status. Pathol Oncol Res. 2012 Oct;18(4):783-92. doi: 10.1007/s12253-011-9485-5. Epub 2012 Jun 24.

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Kim WJ, Lee JW, Quan C, Youn HJ, Kim HM, Bae SC. Nicotinamide inhibits growth of carcinogen induced mouse bladder tumor and human bladder tumor xenograft through up-regulation of RUNX3 and p300. J Urol. 2011 Jun;185(6):2366-75. doi: 10.1016/j.juro.2011.02.017. Epub 2011 Apr 21.

Reference Type BACKGROUND
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Reference Type BACKGROUND
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Reference Type BACKGROUND
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Peck B, Chen CY, Ho KK, Di Fruscia P, Myatt SS, Coombes RC, Fuchter MJ, Hsiao CD, Lam EW. SIRT inhibitors induce cell death and p53 acetylation through targeting both SIRT1 and SIRT2. Mol Cancer Ther. 2010 Apr;9(4):844-55. doi: 10.1158/1535-7163.MCT-09-0971. Epub 2010 Apr 6.

Reference Type BACKGROUND
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McCarthy AR, Sachweh MC, Higgins M, Campbell J, Drummond CJ, van Leeuwen IM, Pirrie L, Ladds MJ, Westwood NJ, Lain S. Tenovin-D3, a novel small-molecule inhibitor of sirtuin SirT2, increases p21 (CDKN1A) expression in a p53-independent manner. Mol Cancer Ther. 2013 Apr;12(4):352-60. doi: 10.1158/1535-7163.MCT-12-0900. Epub 2013 Jan 15.

Reference Type BACKGROUND
PMID: 23322738 (View on PubMed)

Knip M, Douek IF, Moore WP, Gillmor HA, McLean AE, Bingley PJ, Gale EA; European Nicotinamide Diabetes Intervention Trial Group. Safety of high-dose nicotinamide: a review. Diabetologia. 2000 Nov;43(11):1337-45. doi: 10.1007/s001250051536.

Reference Type BACKGROUND
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Gale EA, Bingley PJ, Emmett CL, Collier T; European Nicotinamide Diabetes Intervention Trial (ENDIT) Group. European Nicotinamide Diabetes Intervention Trial (ENDIT): a randomised controlled trial of intervention before the onset of type 1 diabetes. Lancet. 2004 Mar 20;363(9413):925-31. doi: 10.1016/S0140-6736(04)15786-3.

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Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, Gemma A, Harada M, Yoshizawa H, Kinoshita I, Fujita Y, Okinaga S, Hirano H, Yoshimori K, Harada T, Ogura T, Ando M, Miyazawa H, Tanaka T, Saijo Y, Hagiwara K, Morita S, Nukiwa T; North-East Japan Study Group. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010 Jun 24;362(25):2380-8. doi: 10.1056/NEJMoa0909530.

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Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, Zhang S, Wang J, Zhou S, Ren S, Lu S, Zhang L, Hu C, Hu C, Luo Y, Chen L, Ye M, Huang J, Zhi X, Zhang Y, Xiu Q, Ma J, Zhang L, You C. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011 Aug;12(8):735-42. doi: 10.1016/S1470-2045(11)70184-X. Epub 2011 Jul 23.

Reference Type BACKGROUND
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Oh HJ, Bae SC, Oh IJ, Park CK, Jung KM, Kim DM, Lee JW, Kang CK, Park IY, Kim YC. Nicotinamide in Combination with EGFR-TKIs for the Treatment of Stage IV Lung Adenocarcinoma with EGFR Mutations: A Randomized Double-Blind (Phase IIb) Trial. Clin Cancer Res. 2024 Apr 15;30(8):1478-1487. doi: 10.1158/1078-0432.CCR-23-3059.

Reference Type DERIVED
PMID: 38593249 (View on PubMed)

Other Identifiers

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Amina-X-002

Identifier Type: -

Identifier Source: org_study_id

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