Anticancer Activity of Nicotinamide on Lung Cancer

NCT02416739 | Unknown Phase 2 DMC

• 1 other identifier: Amina-X-002
• Study Type: interventional
• Target: 110
• Locations: 1 country
• Sites: 1

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.

Conditions

Non-Small-Cell Lung Carcinoma

Keywords

EGFR mutated lung cancer

Outcome Measures

Primary Outcomes (1)

• Hazard ratio (PFS) of the nicotinamide arm to the placebo arm

  Cox regression analysis

  two year

Secondary Outcomes (3)

• Response rate

  two year

• Difference in quality of life between the nicotinamide arm and the placebo arm

  two year

• Overall survival

  two year

Study Arms (2)

Nicotinamide

EXPERIMENTAL

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

Drug: Nicotinamide

Placebo

PLACEBO COMPARATOR

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

Drug: Nicotinamide

Interventions

Nicotinamide DRUG

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

Also known as: Amina-X

Nicotinamide; Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Il Yeong Park, Ph.D.: lead

Study Sites (1)

Chonnam National University Hwasun Hospital

Hwasun, Chonnam, 58128, South Korea

Location

Related Publications (18)

• 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.

  PMID: 14715269 BACKGROUND

• 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.

  PMID: 11955451 BACKGROUND

• 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.

  PMID: 15780941 BACKGROUND

• 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.

  PMID: 18995842 BACKGROUND

• Lee YS, Lee JW, Jang JW, Chi XZ, Kim JH, Li YH, Kim MK, Kim DM, Choi BS, Kim EG, Chung JH, Lee OJ, Lee YM, Suh JW, Chuang LS, Ito Y, Bae SC. Runx3 inactivation is a crucial early event in the development of lung adenocarcinoma. Cancer Cell. 2013 Nov 11;24(5):603-16. doi: 10.1016/j.ccr.2013.10.003.

  PMID: 24229708 BACKGROUND

• 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.

  PMID: 22729835 BACKGROUND

• 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.

  PMID: 21511279 BACKGROUND

• Park SY, Lee KB, Lee MJ, Bae SC, Jang JJ. Nicotinamide inhibits the early stage of carcinogen-induced hepatocarcinogenesis in mice and suppresses human hepatocellular carcinoma cell growth. J Cell Physiol. 2012 Mar;227(3):899-908. doi: 10.1002/jcp.22799.

  PMID: 21503886 BACKGROUND

• Surjana D, Halliday GM, Damian DL. Role of nicotinamide in DNA damage, mutagenesis, and DNA repair. J Nucleic Acids. 2010 Jul 25;2010:157591. doi: 10.4061/2010/157591.

  PMID: 20725615 BACKGROUND

• 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.

  PMID: 20371709 BACKGROUND

• 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.

  PMID: 23322738 BACKGROUND

• 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.

  PMID: 11126400 BACKGROUND

• 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.

  PMID: 15043959 BACKGROUND

• Petley A, Macklin B, Renwick AG, Wilkin TJ. The pharmacokinetics of nicotinamide in humans and rodents. Diabetes. 1995 Feb;44(2):152-5. doi: 10.2337/diab.44.2.152.

  PMID: 7859933 BACKGROUND

• Schoenfeld DA. Sample-size formula for the proportional-hazards regression model. Biometrics. 1983 Jun;39(2):499-503.

  PMID: 6354290 BACKGROUND

• 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.

  PMID: 20573926 BACKGROUND

• 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.

  PMID: 21783417 BACKGROUND

• 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.

  PMID: 38593249 DERIVED

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung

Interventions

Niacinamide

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Nicotinic Acids; Acids, Heterocyclic; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring

Study Officials

• Il Yeong Park, PhD

  Chungbuk National University

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: April 3, 2015
• First Posted: April 15, 2015
• Study Start: March 1, 2015
• Primary Completion: March 1, 2020
• Study Completion: June 1, 2020
• Last Updated: January 27, 2020

Record last verified: 2020-01

Data Sharing

• IPD Sharing: Will not share

Locations

KR (1)