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Investigational New Drugs

, Volume 35, Issue 2, pp 217–226 | Cite as

Phase I/II study of docetaxel combined with resminostat, an oral hydroxamic acid HDAC inhibitor, for advanced non-small cell lung cancer in patients previously treated with platinum-based chemotherapy

  • Yuichi Tambo
  • Yukio Hosomi
  • Hiroshi Sakai
  • Naoyuki Nogami
  • Shinji Atagi
  • Yasutsuna Sasaki
  • Terufumi Kato
  • Toshiaki Takahashi
  • Takashi Seto
  • Makoto Maemondo
  • Hiroshi Nokihara
  • Ryo Koyama
  • Kazuhiko Nakagawa
  • Tomoya Kawaguchi
  • Yuta Okamura
  • Osamu Nakamura
  • Makoto NishioEmail author
  • Tomohide Tamura
PHASE II STUDIES

Summary

Objectives To determine the recommended dose and efficacy/safety of docetaxel combined with resminostat (DR) in non-small cell lung cancer (NSCLC) patients with previous platinum-based chemotherapy. Materials and Methods A multicenter, open-label, phase I/II study was performed in Japanese patients with stage IIIB/IV or recurrent NSCLC and prior platinum-based chemotherapy. The recommended phase II dose was determined using a standard 3 + 3 dose design in phase I part. Resminostat was escalated from 400 to 600 mg/day and docetaxel fixed at 75 mg/m2. In phase II part, the patients were randomly assigned to docetaxel alone (75 mg/m2) or DR therapy. Docetaxel was administered on day 1 and resminostat on days 1–5 in the DR group. Treatment was repeated every 21 days until progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Results A total of 117 patients (phase I part, 9; phase II part, 108) were enrolled. There was no dose-limiting toxicity in phase I part; the recommended dose for resminostat was 600 mg/day with 75 mg/m2 of docetaxel. In phase II part, median PFS (95% confidence interval [CI]) was 4.2 (2.8–5.7) months with docetaxel group and 4.1 (1.5–5.4) months with DR group (hazard ratio [HR]: 1.354, 95% CI: 0.835–2.195; p = 0.209). Grade ≥ 3 adverse events significantly more common with DR group than docetaxel group were leukopenia, febrile neutropenia, thrombocytopenia, and anorexia. Conclusion In Japanese NSCLC patients previously treated with platinum-based chemotherapy, DR therapy did not improve PFS compared with docetaxel alone and increased toxicity.

Keywords

Histone deacetylase inhibitor Non-small cell lung cancer Resminostat Docetaxel Randomized phase II 

Notes

Acknowledgements

We would like to thank all patients, clinicians, and support staff who participated in this study. We are grateful to Noriyuki Masuda, Fumitaka Nagamura, and Nobuyuki Yamamoto for their helpful advice as members of the DMC, and Kunihisa Miyakawa for performing an extramural review to assess objective responses and PFS.

Compliance with ethical standards

Role of funding source

This study was supported by Yakult Honsha. The study sponsor contributed to the design of the study, data collection, analysis and interpretation of data, writing of the manuscript, and decision to submit the manuscript for publication. All authors had access to all the data in the study and agreed with the decision to submit for publication.

Conflict of interest

Y. Okamura has stock ownership of Yakult. Y. Okamura and O. Nakamura are employees of Yakult. Y. Hosomi has received personal fees from AstraZeneca, Chugai, Eli Lilly, Ono and Taiho. H. Sakai has received grants from Yakult and personal fees from Bristol-Myers Squibb, Chugai, Eli Lilly, Ono and Taiho. N. Nogami has received grants from Yakult and personal fees from Astellas, AstraZeneca, Boehringer Ingelheim, Chugai, Eli Lilly, Ono, Pfizer and Taiho. S. Atagi has received grants and personal fees from AstraZeneca, Boehringer Ingelheim, Chugai, Eli Lilly and Taiho, grants from Merck Serono, Ono, Pfizer and Yakult, and personal fees from Bristol-Myers Squibb. Y. Sasaki has received grants and personal fees from Eisai, Taiho and Yakult, grants from Bristol-Myers Squibb and Novartis, and personal fees from Bayer Yakuhin, Eli Lilly, GlaxoSmithKline, Merck Serono, Nichi-Iko Pharmaceutical, Ono, Sawai and Takeda. T. Kato has received grants and personal fees from AstraZeneca, Boehringer Ingelheim, Chugai, Eli Lilly, Kyowa Hakko Kirin, Ono, Pfizer and Taiho, grants from Abbvie, Astellas, Bristol-Myers Squibb, Daiichi Sankyo, MSD, Parexel, Quintiles, Takeda and Yakult, and personal fees from Roche. T. Takahashi has received grants and personal fees from AstraZeneca, Chugai, Eli Lilly, Ono and Pfizer, grants from MSD, Takeda and Taiho, and personal fees from Boehringer Ingelheim. T. Seto has received grants and personal fees from AstraZeneca, Chugai, Eisai, Eli Lilly, Boehringer Ingelheim, Novartis, Pfizer, Sanofi and Taiho, grants from Astellas, Bayer Yakuhin, Merck Serono, MSD, Verastem and Yakult, and personal fees from Daiichi Sankyo, Fuji Pharma, Hisamitsu, Kyowa Hakko Kirin, Mochida, Nippon Kayaku, Ono, Roche Diagnostics, Showa Yakuhin Kako, Sumitomo Dainippon Pharma and Takeda. H. Nokihara has received grants and personal fees from AstraZeneca, Boehringer Ingelheim, Chugai, Eli Lilly, Ono and Taiho, grants from Astellas, Daiichi Sankyo, Eisai, GlaxoSmithKline, Merck Serono, Novartis, Pfizer, Quintiles and Yakult, and personal fees from Bristol-Myers Squibb and Sanofi. K. Nakagawa has received grants and personal fees from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Kyowa Hakko Kirin, Ono and Pfizer, grants from Eisai, EPS Associate, MSD, Japan Clinical Research Operations, PPD-SNBL, OncoTherapy Science, Quintiles, Takeda, Taiho, and personal fees from Astellas, Eli Lilly, EPS Holdings, Showa Yakuhin Kako and SymBio Pharmaceuticals. M. Nishio has received grants and personal fees from AstraZeneca, Bristol-Myers Squibb, Chugai, Eli Lilly, Ono, Pfizer and Taiho, and grants from Astellas and Novartis. T. Tamura has received personal fees from Astellas, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Eli Lilly, Novartis, Ono, Taiho and Yakult. Y. Tambo, M. Maemondo, R. Koyama and T. Kawaguchi have no conflict of interest to disclose.

Statement of human rights

This study was performed in accordance with the Declaration of Helsinki and Good Clinical Practice and was approved by the institutional review boards of all participating institutions.

Informed consent

All patients provided written informed consent before enrollment in this study.

References

  1. 1.
    Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A (2015) Global cancer statistics, 2012. CA Cancer J Clin 65:87–108CrossRefPubMedGoogle Scholar
  2. 2.
    Li T, Kung HJ, Mack PC, Gandara DR (2013) Genotyping and genomic profiling of non-small-cell lung cancer: implications for current and future therapies. J Clin Oncol 31:1039–1049CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Stinchcombe TE, Socinski MA (2009) Current treatments for advanced stage non-small cell lung cancer. Proc Am Thorac Soc 6:233–241CrossRefPubMedGoogle Scholar
  4. 4.
    Shepherd FA, Dancey J, Ramlau R, Mattson K, Gralla R, O’Rourke M, Levitan N, Gressot L, Vincent M, Burkes R, Coughlin S, Kim Y, Berille J (2000) Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 18:2095–2103CrossRefPubMedGoogle Scholar
  5. 5.
    Hanna N, Shepherd FA, Fossella FV, Pereira JR, De Marinis F, von Pawel J, Gatzemeier U, Tsao TC, Pless M, Muller T, Lim HL, Desch C, Szondy K, Gervais R, Shaharyar, Manegold C, Paul S, Paoletti P, Einhorn L, Bunn PA Jr (2004) Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 22:1589–1597CrossRefPubMedGoogle Scholar
  6. 6.
    Shepherd FA, Pereira JR, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, Campos D, Maoleekoonpiroj S, Smylie M, Martins R, van Kooten M, Dediu M, Findlay B, Tu D, Johnston D, Bezjak A, Clark G, Santabárbara P, Seymour L, National Cancer Institute of Canada Clinical Trials Group (2005) Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 353:123–132CrossRefPubMedGoogle Scholar
  7. 7.
    Kim ES, Hirsh V, Mok T, Socinski MA, Gervais R, Wu YL, Li LY, Watkins CL, Sellers MV, Lowe ES, Sun Y, Liao ML, Osterlind K, Reck M, Armour AA, Shepherd FA, Lippman SM, Douillard JY (2008) Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet 372:1809–1818CrossRefPubMedGoogle Scholar
  8. 8.
    Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WE, Poddubskaya E, Antonia S, Pluzanski A, Vokes EE, Holgado E, Waterhouse D, Ready N, Gainor J, Arén Frontera O, Havel L, Steins M, Garassino MC, Aerts JG, Domine M, Paz-Ares L, Reck M, Baudelet C, Harbison CT, Lestini B, Spigel DR (2015) Nivolumab versus docetaxel in advanced squamous-cell Non-small-cell lung cancer. N Engl J Med 373:123–135CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, Barlesi F, Kohlhäufl M, Arrieta O, Burgio MA, Fayette J, Lena H, Poddubskaya E, Gerber DE, Gettinger SN, Rudin CM, Rizvi N, Crinò L, Blumenschein GR Jr, Antonia SJ, Dorange C, Harbison CT, Graf Finckenstein F, Brahmer JR (2015) Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med 373:1627–1639CrossRefPubMedGoogle Scholar
  10. 10.
    Reck M, Kaiser R, Mellemgaard A, Douillard JY, Orlov S, Krzakowski M, von Pawel J, Gottfried M, Bondarenko I, Liao M, Gann CN, Barrueco J, Gaschler-Markefski B, Novello S, LUME-Lung 1 Study Group (2014) Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-lung 1): a phase 3, double-blind, randomised controlled trial. Lancet Oncol 15:143–155CrossRefPubMedGoogle Scholar
  11. 11.
    Garon EB, Ciuleanu TE, Arrieta O, Prabhash K, Syrigos KN, Goksel T, Park K, Gorbunova V, Kowalyszyn RD, Pikiel J, Czyzewicz G, Orlov SV, Lewanski CR, Thomas M, Bidoli P, Dakhil S, Gans S, Kim JH, Grigorescu A, Karaseva N, Reck M, Cappuzzo F, Alexandris E, Sashegyi A, Yurasov S, Pérol M (2014) Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet 384:665–673Google Scholar
  12. 12.
    Workman JL, Kingston RE (1998) Alteration of nucleosome structure as a mechanism of transcriptional regulation. Annu Rev Biochem 67:545–579CrossRefPubMedGoogle Scholar
  13. 13.
    Richon VM, Sandhoff TW, Rifkind RA, Marks PA (2000) Histone deacetylase inhibitor selectively induces p21WAF1 expression and gene-associated histone acetylation. Proc Natl Acad Sci USA 97:10014–10019Google Scholar
  14. 14.
    Jones PA, Baylin SB (2002) The fundamental role of epigenetic events in cancer. Nat Rev Genet 3:415–428CrossRefPubMedGoogle Scholar
  15. 15.
    Arts GJ, Langemeijer E, Tissingh R, Ma L, Pavliska H, Dokic K, Dooijes R, Mesić E, Clasen R, Michiels F, van der Schueren J, Lambrecht M, Herman S, Brys R, Thys K, Hoffmann M, Tomme P, van Es H (2003) Adenoviral vectors expressing siRNAs for discovery and validation of gene function. Genome Res 13:2325–2332CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Falkenberg KJ, Johnstone RW (2014) Histone deacetylases and their inhibitors in cancer, neurological diseases and immune disorders. Nat Rev Drug Discov 13:673–691CrossRefPubMedGoogle Scholar
  17. 17.
    Olsen EA, Kim YH, Kuzel TM, Pacheco TR, Foss FM, Parker S, Frankel SR, Chen C, Ricker JL, Arduino JM, Duvic M (2007) Phase IIb multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma. J Clin Oncol 25:3109–3115CrossRefPubMedGoogle Scholar
  18. 18.
    Whittaker SJ, Demierre MF, Kim EJ, Rook AH, Lerner A, Duvic M, Scarisbrick J, Reddy S, Robak T, Becker JC, Samtsov A, McCulloch W, Kim YH (2010) Final results from a multicenter, international, pivotal study of romidepsin in refractory cutaneous T-cell lymphoma. J Clin Oncol 28:4485–4491CrossRefPubMedGoogle Scholar
  19. 19.
    Coiffier B, Pro B, Prince HM, Foss F, Sokol L, Greenwood M, Caballero D, Borchmann P, Morschhauser F, Wilhelm M, Pinter-Brown L, Padmanabhan S, Shustov A, Nichols J, Carroll S, Balser J, Balser B, Horwitz S (2012) Results from a pivotal, open-label, phase II study of romidepsin in relapsed or refractory peripheral T-cell lymphoma after prior systemic therapy. J Clin Oncol 30:631–636CrossRefPubMedGoogle Scholar
  20. 20.
    O'Connor OA, Horwitz S, Masszi T, Van Hoof A, Brown P, Doorduijn J, Hess G, Jurczak W, Knoblauch P, Chawla S, Bhat G, Choi MR, Walewski J, Savage K, Foss F, Allen LF, Shustov A (2015) Belinostat in patients with relapsed or refractory peripheral T-cell lymphoma: results of the pivotal phase II BELIEF (CLN-19) study. J Clin Oncol 33:2492–2499CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Richardson PG, Hungria VT, Yoon SS, Beksac M, Dimopoulos MA, Elghandour A, Jedrzejczak WW, Guenther A, Nakorn TN, Siritanaratkul N, Schlossman RL, Hou J, Moreau P, Lonial S, Lee JH, Einsele H, Sopala M, Bengoudifa BR, Corrado C, Binlich F, San-Miguel JF (2016) Panobinostat plus bortezomib and dexamethasone in previously treated multiple myeloma: outcomes by prior treatment. Blood 127:713–721CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Finnin MS, Donigian JR, Cohen A, Richon VM, Rifkind RA, Marks PA, Breslow R, Pavletich NP (1999) Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors. Nature 401:188–193CrossRefPubMedGoogle Scholar
  23. 23.
    Kitazono S, Fujiwara Y, Nakamichi S, Mizugaki H, Nokihara H, Yamamoto N, Yamada Y, Inukai E, Nakamura O, Tamura T (2015) A phase I study of resminostat in Japanese patients with advanced solid tumors. Cancer Chemother Pharmacol 75:1155–1161CrossRefPubMedGoogle Scholar
  24. 24.
    Takagi A, Konishi H, Tsugane M, Taniguchi K, Takahashi H, Inutake Y, Watanabe A, Kodaira H, Matsuzaki T (2014) A novel and oral histone deacetylase inhibitor, resminostat, effectively suppresses the growth of non-small cell lung cancer in a xenograft mouse model. Cancer Res 74 (suppl19; abstr 5534).Google Scholar
  25. 25.
    Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J (2009) New response evaluation criteria in solid tumors: revised RECIST guideline (version 1.1). Eur J Cancer 45:228–247CrossRefPubMedGoogle Scholar
  26. 26.
    Bitzer M, Horger M, Giannini EG, Ganten TM, Wörns MA, Siveke JT, Dollinger MM, Gerken G, Scheulen ME, Wege H, Zagonel V, Cillo U, Trevisani F, Santoro A, Montesarchio V, Malek NP, Holzapfel J, Herz T, Ammendola AS, Pegoraro S, Hauns B, Mais A, Lauer UM, Henning SW, Hentsch B (2016) Resminostat plus sorafenib as second-line therapy of advanced hepatocellular carcinoma - the SHELTER study. J Hepatol 65:280–288CrossRefPubMedGoogle Scholar
  27. 27.
    Mandl-Weber S, Meinel FG, Jankowsky R, Oduncu F, Schmidmaier R, Baumann P (2010) The novel inhibitor of histone deacetylase resminostat (RAS2410) inhibits proliferation and induces apoptosis in multiple myeloma (MM) cells. Br J Haematol 149:518–528CrossRefPubMedGoogle Scholar
  28. 28.
    Costa C, Molina MA, Drozdowskyj A, Giménez-Capitán A, Bertran-Alamillo J, Karachaliou N, Gervais R, Massuti B, Wei J, Moran T, Majem M, Felip E, Carcereny E, Garcia-Campelo R, Viteri S, Taron M, Ono M, Giannikopoulos P, Bivona T, Rosell R (2014) The impact of EGFR T790 M mutations and BIM mRNA expression on outcome in patients with EGFR-mutant NSCLC treated with erlotinib or chemotherapy in the randomized phase III EURTAC trial. Clin Cancer Res 20:2001–2010CrossRefPubMedGoogle Scholar
  29. 29.
    Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods 25:402–408CrossRefPubMedGoogle Scholar
  30. 30.
    Taguchi T, Furue H, Niitani H, Ishitani K, Kanamaru R, Hasegawa K, Ariyoshi Y, Noda K, Furuse K, Fukuoka M, Yakushiji M, Kashimura M (1994) Phase I clinical trial of RP56976 (docetaxel) a new anticancer drug. Jpn J Cancer Chemother 21:1997–2005Google Scholar
  31. 31.
    Yoh K, Hosomi Y, Kasahara K, Yamada K, Takahashi T, Yamamoto N, Nishio M, Ohe Y, Koue T, Nakamura T, Enatsu S, Lee P, Ferry D, Tamura T, Nakagawa K (2016) A randomized, double-blind, phase II study of ramucirumab plus docetaxel vs placebo plus docetaxel in Japanese patients with stage IV non-small cell lung cancer after disease progression on platinum-based therapy. Lung Cancer 99:186–193CrossRefPubMedGoogle Scholar
  32. 32.
    Ramalingam SS, Maitland ML, Frankel P, Argiris AE, Koczywas M, Gitlitz B, Thomas S, Espinoza-Delgado I, Vokes EE, Gandara DR, Belani CP (2010) Carboplatin and paclitaxel in combination with either vorinostat or placebo for first-line therapy of advanced non-small-cell lung cancer. J Clin Oncol 28:56–62CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Yuichi Tambo
    • 1
  • Yukio Hosomi
    • 2
  • Hiroshi Sakai
    • 3
  • Naoyuki Nogami
    • 4
  • Shinji Atagi
    • 5
  • Yasutsuna Sasaki
    • 6
  • Terufumi Kato
    • 7
  • Toshiaki Takahashi
    • 8
  • Takashi Seto
    • 9
  • Makoto Maemondo
    • 10
  • Hiroshi Nokihara
    • 11
  • Ryo Koyama
    • 12
  • Kazuhiko Nakagawa
    • 13
  • Tomoya Kawaguchi
    • 14
  • Yuta Okamura
    • 15
  • Osamu Nakamura
    • 15
  • Makoto Nishio
    • 1
    Email author
  • Tomohide Tamura
    • 16
  1. 1.Department of Thoracic Medical OncologyThe Cancer Institute Hospital of Japanese Foundation for Cancer ResearchTokyoJapan
  2. 2.Department of Thoracic Oncology and Respiratory MedicineTokyo Metropolitan Cancer and Infectious Diseases Center Komagome HospitalTokyoJapan
  3. 3.Division of Thoracic OncologySaitama Cancer CenterSaitamaJapan
  4. 4.Department of Thoracic Oncology and MedicineNational Hospital Organization Shikoku Cancer CenterEhimeJapan
  5. 5.Department of Thoracic OncologyNational Hospital Organization Kinki-chuo Chest Medical CenterOsakaJapan
  6. 6.Division of Medical OncologyShowa University School of MedicineTokyoJapan
  7. 7.Department of Respiratory MedicineKanagawa Cardiovascular and Respiratory CenterKanagawaJapan
  8. 8.Division of Thoracic OncologyShizuoka Cancer CenterShizuokaJapan
  9. 9.Department of Thoracic OncologyNational Kyushu Cancer CenterFukuokaJapan
  10. 10.Department of Respiratory MedicineMiyagi Cancer CenterMiyagiJapan
  11. 11.Department of Thoracic OncologyNational Cancer Center HospitalTokyoJapan
  12. 12.Department of Respiratory MedicineJuntendo University Graduate School of MedicineTokyoJapan
  13. 13.Department of Medical OncologyKinki University Faculty of MedicineOsakaJapan
  14. 14.Department of Respiratory MedicineOsaka City University HospitalOsakaJapan
  15. 15.Pharmaceutical Research and Development DepartmentYakult Honsha Co., Ltd.TokyoJapan
  16. 16.Thoracic CenterSt. Luke’s International HospitalTokyoJapan

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