Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Investigational New Drugs
Published in: Investigational New Drugs 2/2017

01-04-2017 | PHASE II STUDIES

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

Authors: 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 Nishio, Tomohide Tamura

Published in: Investigational New Drugs | Issue 2/2017

Login to get access

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.
Literature
1.
Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A (2015) Global cancer statistics, 2012. CA Cancer J Clin 65:87–108CrossRefPubMed
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 31:1039–1049CrossRefPubMedPubMedCentral
3.
Stinchcombe TE, Socinski MA (2009) Current treatments for advanced stage non-small cell lung cancer. Proc Am Thorac Soc 6:233–241CrossRefPubMed
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 18:2095–2103CrossRefPubMed
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 22:1589–1597CrossRefPubMed
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 353:123–132CrossRefPubMed
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 372:1809–1818CrossRefPubMed
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 373:123–135CrossRefPubMedPubMedCentral
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 373:1627–1639CrossRefPubMed
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 15:143–155CrossRefPubMed
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 384:665–673
12.
Workman JL, Kingston RE (1998) Alteration of nucleosome structure as a mechanism of transcriptional regulation. Annu Rev Biochem 67:545–579CrossRefPubMed
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 97:10014–10019
14.
Jones PA, Baylin SB (2002) The fundamental role of epigenetic events in cancer. Nat Rev Genet 3:415–428CrossRefPubMed
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 13:2325–2332CrossRefPubMedPubMedCentral
16.
Falkenberg KJ, Johnstone RW (2014) Histone deacetylases and their inhibitors in cancer, neurological diseases and immune disorders. Nat Rev Drug Discov 13:673–691CrossRefPubMed
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 25:3109–3115CrossRefPubMed
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 28:4485–4491CrossRefPubMed
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 30:631–636CrossRefPubMed
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 33:2492–2499CrossRefPubMedPubMedCentral
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 127:713–721CrossRefPubMedPubMedCentral
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 401:188–193CrossRefPubMed
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 75:1155–1161CrossRefPubMed
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).
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 45:228–247CrossRefPubMed
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 65:280–288CrossRefPubMed
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 149:518–528CrossRefPubMed
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 20:2001–2010CrossRefPubMed
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 25:402–408CrossRefPubMed
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 21:1997–2005
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 99:186–193CrossRefPubMed
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 28:56–62CrossRefPubMed
Metadata
Title
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
Authors
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 Nishio
Tomohide Tamura
Publication date
01-04-2017
Publisher
Springer US
Published in
Investigational New Drugs / Issue 2/2017
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI
https://doi.org/10.1007/s10637-017-0435-2

Other articles of this Issue 2/2017

Investigational New Drugs 2/2017 Go to the issue

PHASE I STUDIES

Phase I study of Nivolumab, an anti-PD-1 antibody, in patients with malignant solid tumors

PRECLINICAL STUDIES

Pharmacokinetics and derivation of an anticancer dosing regimen for the novel anti-cancer agent isobutyl-deoxynyboquinone (IB-DNQ), a NQO1 bioactivatable molecule, in the domestic felid species

PHASE II STUDIES

Phase II study of the antibody-drug conjugate TAK-264 (MLN0264) in patients with metastatic or recurrent adenocarcinoma of the stomach or gastroesophageal junction expressing guanylyl cyclase C

PRECLINICAL STUDIES

Targeting specificity protein 1 transcription factor and survivin using tolfenamic acid for inhibiting Ewing sarcoma cell growth

PHASE II STUDIES

A phase II study of carboplatin plus weekly paclitaxel with bevacizumab for elderly patients with non-squamous non-small-cell lung cancer (NEJ016)

PRECLINICAL STUDIES

Alofanib, an allosteric FGFR2 inhibitor, has potent effects on ovarian cancer growth in preclinical studies
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits