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Romidepsin in Japanese patients with relapsed or refractory peripheral T-cell lymphoma: a phase I/II and pharmacokinetics study

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Abstract

This phase I/II multicenter study evaluated romidepsin treatment in Japanese patients with relapsed/refractory peripheral T-cell lymphoma (PTCL) or cutaneous T-cell lymphoma (CTCL). Patients aged ≥20 years received romidepsin via a 4-h intravenous infusion on days 1, 8, and 15 of each 28-day cycle. Phase I used a 3 + 3 design to identify any dose-limiting toxicity (DLT) for regimens of romidepsin 9 and 14 mg/m2. The primary endpoints for phase I and II were DLT and overall response rate (ORR), respectively. Intent-to-treat patients were those who received ≥1 romidepsin dose (PTCL, n = 48; CTCL, n = 2). In phase I, none of the patients (n = 3, 9 mg/m2; n = 6, 14 mg/m2) exhibited DLT. In phase II, 40 patients with PTCL were treated with 14 mg/m2 romidepsin. The most common treatment-emergent grade ≥3 adverse events were lymphopenia (74%), neutropenia (54%), leukopenia (46%), and thrombocytopenia (38%). Patients in phase II showed a 43% ORR, including 25% complete responses. Median progression-free survival was 5.6 months and median duration of response was 11.1 months. This phase I/II study identified a well-tolerated dose of romidepsin, with an acceptable toxicity profile and clinically meaningful efficacy in Japanese patients with relapsed/refractory PTCL.

ClinicalTrials.gov Identifier NCT01456039.

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References

  1. Karlin L, Coiffier B. The changing landscape of peripheral T-cell lymphoma in the era of novel therapies. Semin Hematol. 2014;51:25–34.

    Article  PubMed  Google Scholar 

  2. Vose J, Armitage J, Weisenburger D, International TCLP. International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. J Clin Oncol. 2008;26:4124–30.

    Article  PubMed  Google Scholar 

  3. Weisenburger DD, Savage KJ, Harris NL, Gascoyne RD, Jaffe ES, MacLennan KA, et al. Peripheral T-cell lymphoma, not otherwise specified: a report of 340 cases from the International Peripheral T-cell Lymphoma Project. Blood. 2011;117:3402–8.

    Article  CAS  PubMed  Google Scholar 

  4. Mak V, Hamm J, Chhanabhai M, Shenkier T, Klasa R, Sehn LH, et al. Survival of patients with peripheral T-cell lymphoma after first relapse or progression: spectrum of disease and rare long-term survivors. J Clin Oncol. 2013;31:1970–6.

    Article  CAS  PubMed  Google Scholar 

  5. SEER Cancer Statistics Factsheets: Non-Hodgkin Lymphoma. National Cancer Institute. Bethesda, MD. https://seer.cancer.gov/statfacts/html/nhl.html. Accessed 17 Jan 2017.

  6. Suzuki R. Guideline for T/NK-cell lymphoma. Rinsho Ketsueki. 2013;54:1764–9.

    PubMed  Google Scholar 

  7. Pro B, Advani R, Brice P, Bartlett NL, Rosenblatt JD, Illidge T, et al. Brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large-cell lymphoma: results of a phase II study. J Clin Oncol. 2012;30:2190–6.

    Article  CAS  PubMed  Google Scholar 

  8. Lunning MA. Treatment of peripheral T-cell lymphoma: many shades of gray. Oncology (Williston Park). 2015;29:545–50.

    PubMed  Google Scholar 

  9. Ogura M, Ishida T, Hatake K, Taniwaki M, Ando K, Tobinai K, et al. Multicenter phase II study of mogamulizumab (KW-0761), a defucosylated anti-cc chemokine receptor 4 antibody, in patients with relapsed peripheral T-cell lymphoma and cutaneous T-cell lymphoma. J Clin Oncol. 2014;32:1157–63.

    Article  CAS  PubMed  Google Scholar 

  10. Zinzani PL, Karlin L, Radford J, Caballero D, Fields P, Chamuleau ME, et al. European phase II study of mogamulizumab, an anti-CCR4 monoclonal antibody, in relapsed/refractory peripheral T-cell lymphoma. Haematologica. 2016;101:e407–10.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Ueda H, Manda T, Matsumoto S, Mukumoto S, Nishigaki F, Kawamura I, et al. FR901228, a novel antitumor bicyclic depsipeptide produced by Chromobacterium violaceum No. 968. III. Antitumor activities on experimental tumors in mice. J Antibiot (Tokyo). 1994;47:315–23.

    Article  CAS  Google Scholar 

  12. Ueda H, Nakajima H, Hori Y, Fujita T, Nishimura M, Goto T, et al. FR901228, a novel antitumor bicyclic depsipeptide produced by Chromobacterium violaceum No. 968. I. Taxonomy, fermentation, isolation, physico-chemical and biological properties, and antitumor activity. J Antibiot (Tokyo). 1994;47:301–10.

    Article  CAS  Google Scholar 

  13. Nakajima H, Kim YB, Terano H, Yoshida M, Horinouchi S. FR901228, a potent antitumor antibiotic, is a novel histone deacetylase inhibitor. Exp Cell Res. 1998;241:126–33.

    Article  CAS  PubMed  Google Scholar 

  14. Hartlapp I, Pallasch C, Weibert G, Kemkers A, Hummel M, Re D. Depsipeptide induces cell death in Hodgkin lymphoma-derived cell lines. Leuk Res. 2009;33:929–36.

    Article  CAS  PubMed  Google Scholar 

  15. Valdez BC, Brammer JE, Li Y, Murray D, Liu Y, Hosing C, et al. Romidepsin targets multiple survival signaling pathways in malignant T cells. Blood Cancer J. 2015;5:e357.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Graham C, Tucker C, Creech J, Favours E, Billups CA, Liu T, et al. Evaluation of the antitumor efficacy, pharmacokinetics, and pharmacodynamics of the histone deacetylase inhibitor depsipeptide in childhood cancer models in vivo. Clin Cancer Res. 2006;12:223–34.

    Article  CAS  PubMed  Google Scholar 

  17. Piekarz RL, Robey RW, Zhan Z, Kayastha G, Sayah A, Abdeldaim AH, et al. T-cell lymphoma as a model for the use of histone deacetylase inhibitors in cancer therapy: impact of depsipeptide on molecular markers, therapeutic targets, and mechanisms of resistance. Blood. 2004;103:4636–43.

    Article  CAS  PubMed  Google Scholar 

  18. Sasakawa Y, Naoe Y, Inoue T, Sasakawa T, Matsuo M, Manda T, et al. Effects of FK228, a novel histone deacetylase inhibitor, on human lymphoma U-937 cells in vitro and in vivo. Biochem Pharmacol. 2002;64:1079–90.

    Article  CAS  PubMed  Google Scholar 

  19. Murata M, Towatari M, Kosugi H, Tanimoto M, Ueda R, Saito H, et al. Apoptotic cytotoxic effects of a histone deacetylase inhibitor, FK228, on malignant lymphoid cells. Jpn J Cancer Res. 2000;91:1154–60.

    Article  CAS  PubMed  Google Scholar 

  20. Kosugi H, Ito M, Yamamoto Y, Towatari M, Ito M, Ueda R, et al. In vivo effects of a histone deacetylase inhibitor, FK228, on human acute promyelocytic leukemia in NOD/Shi-scid/scid mice. Jpn J Cancer Res. 2001;92:529–36.

    Article  CAS  PubMed  Google Scholar 

  21. Sato N, Ohta T, Kitagawa H, Kayahara M, Ninomiya I, Fushida S, et al. FR901228, a novel histone deacetylase inhibitor, induces cell cycle arrest and subsequent apoptosis in refractory human pancreatic cancer cells. Int J Oncol. 2004;24:679–85.

    CAS  PubMed  Google Scholar 

  22. Klisovic DD, Katz SE, Effron D, Klisovic MI, Wickham J, Parthun MR, et al. Depsipeptide (FR901228) inhibits proliferation and induces apoptosis in primary and metastatic human uveal melanoma cell lines. Investig Ophthalmol Vis Sci. 2003;44:2390–8.

    Article  Google Scholar 

  23. Marshall JL, Rizvi N, Kauh J, Dahut W, Figuera M, Kang MH, et al. A phase I trial of depsipeptide (FR901228) in patients with advanced cancer. J Exp Ther Oncol. 2002;2:325–32.

    Article  CAS  PubMed  Google Scholar 

  24. Sandor V, Bakke S, Robey RW, Kang MH, Blagosklonny MV, Bender J, et al. Phase I trial of the histone deacetylase inhibitor, depsipeptide (FR901228, NSC 630176), in patients with refractory neoplasms. Clin Cancer Res. 2002;8:718–28.

    CAS  PubMed  Google Scholar 

  25. Amiri-Kordestani L, Luchenko V, Peer CJ, Ghafourian K, Reynolds J, Draper D, et al. Phase I trial of a new schedule of romidepsin in patients with advanced cancers. Clin Cancer Res. 2013;19:4499–507.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Piekarz RL, Frye R, Prince HM, Kirschbaum MH, Zain J, Allen SL, et al. Phase 2 trial of romidepsin in patients with peripheral T-cell lymphoma. Blood. 2011;117:5827–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Coiffier B, Pro B, Prince HM, Foss F, Sokol L, Greenwood M, et al. 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. 2012;30:631–6.

    Article  CAS  PubMed  Google Scholar 

  28. Coiffier B, Pro B, Prince HM, Foss F, Sokol L, Greenwood M, et al. Romidepsin for the treatment of relapsed/refractory peripheral T-cell lymphoma: pivotal study update demonstrates durable responses. J Hematol Oncol. 2014;7:11.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Cheson BD, Horning SJ, Coiffier B, Shipp MA, Fisher RI, Connors JM, et al. Report of an international workshop to standardize response criteria for non-Hodgkin’s lymphomas. NCI Sponsored International Working Group. J Clin Oncol. 1999;17:1244.

    Article  CAS  PubMed  Google Scholar 

  30. JCOG-LSG. JCOG-LSG manual of clinical research for lymphoma and myeloma. 1st ed. Tokyo, Japan: The Japan Foundation for Aging and Health; 2003. p. 68–73.

  31. Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, et al. Revised response criteria for malignant lymphoma. J Clin Oncol. 2007;25:579–86.

    Article  PubMed  Google Scholar 

  32. Hashimoto K, Kobayashi Y, Asakura Y, Mori M, Azuma T, Maruyama D, et al. Pneumocystis jiroveci pneumonia in relation to CD4+ lymphocyte count in patients with B-cell non-Hodgkin lymphoma treated with chemotherapy. Leuk Lymphoma. 2010;51:1816–21.

    Article  CAS  PubMed  Google Scholar 

  33. Swerdlow SH, Campo E, Harris NLE. WHO classification of tumours of haematopoietic and lymphoid tissues. 4th ed. Lyon: IARC; 2008.

    Google Scholar 

  34. Kim SJ, Kim JH, Ki CS, Ko YH, Kim JS, Kim WS. Epstein–Barr virus reactivation in extranodal natural killer/T-cell lymphoma patients: a previously unrecognized serious adverse event in a pilot study with romidepsin. Ann Oncol. 2016;27:508–13.

    Article  CAS  PubMed  Google Scholar 

  35. Bates SE, Zhan Z, Steadman K, Obrzut T, Luchenko V, Frye R, et al. Laboratory correlates for a phase II trial of romidepsin in cutaneous and peripheral T-cell lymphoma. Br J Haematol. 2010;148:256–67.

    Article  CAS  PubMed  Google Scholar 

  36. Woo S, Gardner ER, Chen X, Ockers SB, Baum CE, Sissung TM, et al. Population pharmacokinetics of romidepsin in patients with cutaneous T-cell lymphoma and relapsed peripheral T-cell lymphoma. Clin Cancer Res. 2009;15:1496–503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. O’Connor OA, Pro B, Pinter-Brown L, Bartlett N, Popplewell L, Coiffier B, et al. Pralatrexate in patients with relapsed or refractory peripheral T-cell lymphoma: results from the pivotal PROPEL study. J Clin Oncol. 2011;29:1182–9.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Morschhauser F, Fitoussi O, Haioun C, Thieblemont C, Quach H, Delarue R, et al. A phase 2, multicentre, single-arm, open-label study to evaluate the safety and efficacy of single-agent lenalidomide (Revlimid) in subjects with relapsed or refractory peripheral T-cell non-Hodgkin lymphoma: the EXPECT trial. Eur J Cancer. 2013;49:2869–76.

    Article  CAS  PubMed  Google Scholar 

  39. Ogura M, Imaizumi Y, Uike N, Asou N, Utsunomiya A, Uchida T, et al. Lenalidomide in relapsed adult T-cell leukaemia-lymphoma or peripheral T-cell lymphoma (ATLL-001): a phase 1, multicentre, dose-escalation study. Lancet Haematol. 2016;3:e107–18.

    Article  PubMed  Google Scholar 

  40. Tsukasaki K, Tobinai K, Uchida T, Maeda Y, Shibayama H, Nagai H, et al. Phase 1/2 study of forodesine in patients with relapsed peripheral T-cell lymphoma. J Clin Oncol. 2016. doi:10.1200/JCO.2016.34.15

    PubMed  Google Scholar 

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Acknowledgements

All authors performed and/or designed the research study, analyzed the data, contributed to the development and revision of the manuscript, and approved the final version for submission. The authors thank the patients, their family members, and collaborators from participating institutions and Celgene Corporation. Thank you to Norio Komatsu, M.D., Ph.D., for providing medical expertise; Kazuma Ohyashiki, M.D., Ph.D., Jin Takeuchi, M.D., Ph.D., and Noriko Usui, M.D., who served on the efficacy and safety evaluation committee (ESEC); Takashi Terauchi, M.D., Ukihide Tateishi, M.D., and Mitsuaki Tatsumi, M.D., who served on the Independent Radiological Review Committee (IRRC); Yoshihiro Matsuno, M.D., Ph.D., Akiko Maeshima, M.D., Ph.D., and Kouichi Ohshima, M.D., Ph.D., who were the central pathologists for the study; Masaaki Shoji, M.D., who was the cardiologist for the study; and Junji Suzumiya, M.D., Ph.D., who served as an independent efficacy reviewer. Medical writing support was provided by Bio Connections LLC, and funded by Celgene Corporation; the authors were fully responsible for content and editorial decisions for this manuscript.

Author information

Author notes

  1. Kenichi Ishizawa

    Present address: Hematology and Cell Therapy, Yamagata University Faculty of Medicine, Yamagata, Japan

  2. Takayuki Ikezoe

    Present address: Department of Hematology, Fukushima Medical University School of Medicine, Fukushima, Japan

Authors and Affiliations

  1. Department of Hematology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, Japan

    Dai Maruyama & Kensei Tobinai

  2. Department of Hematology, Tokai Central Hospital, Gifu, Japan

    Michinori Ogura

  3. Department of Hematology and Oncology, Nagoya Daini Red Cross Hospital, Aichi, Japan

    Michinori Ogura & Toshiki Uchida

  4. Department of Hematology and Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan

    Kiyohiko Hatake

  5. Department of Hematology, Kyoto Prefectural University of Medicine, Kyoto, Japan

    Masafumi Taniwaki

  6. Department of Hematology/Oncology, Tokai University School of Medicine, Kanagawa, Japan

    Kiyoshi Ando

  7. Department of Hematology and Oncology, National Cancer Center Hospital East, Chiba, Japan

    Kunihiro Tsukasaki

  8. Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Aichi, Japan

    Takashi Ishida

  9. Department of Hematology, Sapporo Hokuyu Hospital, Hokkaido, Japan

    Naoki Kobayashi

  10. Department of Hematology and Rheumatology, Tohoku University Hospital, Miyagi, Japan

    Kenichi Ishizawa

  11. Department of Hematology and Rheumatology, Kinki University Hospital, Faculty of Medicine, Osaka, Japan

    Yoichi Tatsumi

  12. Department of Hematology and Oncology, Kyushu University Hospital, Fukuoka, Japan

    Koji Kato

  13. Department of Hematology, Chugoku Central Hospital, Hiroshima, Japan

    Toru Kiguchi

  14. Department of Hematology and Respiratory Medicine, Kochi Medical School Hospital, Kochi, Japan

    Takayuki Ikezoe

  15. Celgene Corporation, Summit, NJ, USA

    Eric Laille

  16. Celgene K.K., Tokyo, Japan

    Tokihiro Ro, Hiromi Tamakoshi, Sanae Sakurai & Tomoko Ohtsu

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  1. Dai Maruyama
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  2. Kensei Tobinai
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  3. Michinori Ogura
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Correspondence to Dai Maruyama.

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Conflict of interest

D.M. reports personal fees from Celgene during the conduct of the study; and outside the submitted work, honoraria and research funding from Takeda, Janssen, Eisai, Celgene, Kyowa Hakko Kirin, Ono, Mundipharma, and Chugai; research funding from GlaxoSmithKline, Servier, AbbVie, and MSD; and honoraria from Biomedis International, sanofi, Fujifilm, and Mochida Pharmaceutical Co. Ltd. K.To. reports grants and personal fees from Eisai, Takeda, Mundipharma, Kyowa Hakko Kirin, and Celgene; personal fees from HUYA Bioscience International during the conduct of the study; and outside the submitted work, personal fees from Zenyaku Kogyo; grants and personal fees from Janssen, Chugai Pharma, and Ono Pharmaceutical; and grants from GlaxoSmithKline, Servier, and AbbVie. M.O. reports research funding from SymBio and Celltrion; honoraria from AstraZeneca, Takeda, and Celgene; and advisory board personal fees from Mundipharma, MeijiSeika Pharma, and Celltrion outside of the submitted work. K.H. reports relationships/conditions/circumstances that may influence this work from AbbVie, Gilead, Celgene, Solasia, Pfizer, BMS, Janssen, Ono, and Chugai. K.Ts. reports grants from Celgene, Takeda, MundiPharma, and Chugai; and personal lecture fees from Zennyakukogyo, HUYA Biosciences, Chugai, and Kyowa Kirin outside of the submitted work. T.Is. reports personal fees from Celgene K.K. during the conduct of the study; and outside of the submitted work grants from Kyowa Hakko Kirin Co. Ltd, Bayer Pharma AG, and J-pharma Co. Ltd; and honoraria from Kyowa Hakko Kirin Co. Ltd. K.Is. reports grants and personal fees from Kyowa Kirin and Takeda during the conduct of the study; and personal fees from Cyugai, Janssen, Novartis, Ono, and Pfizer outside the submitted work. E.L., T.R., H.T., S.S., and T.O. are employed by and have received stock ownership from Celgene Corporation. T.U., K.A., M.T., N.K., Y.T., K.K., T.K., and T.Ik., have no relevant financial relationships to disclose. The study was designed under the responsibility of Celgene Corporation; the study was funded by Celgene K. K. (Tokyo, Japan); Romidepsin was provided by Celgene K.K. (Tokyo, Japan). Celgene K. K. (Tokyo, Japan) collected and analyzed the data and contributed to the interpretation of the study. All authors had full access to all of the data in the study and had final responsibility for the decision to submit for publication.

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Maruyama, D., Tobinai, K., Ogura, M. et al. Romidepsin in Japanese patients with relapsed or refractory peripheral T-cell lymphoma: a phase I/II and pharmacokinetics study. Int J Hematol 106, 655–665 (2017). https://doi.org/10.1007/s12185-017-2286-1

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  • DOI: https://doi.org/10.1007/s12185-017-2286-1

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