Author Manuscript Published OnlineFirst on November 26, 2019; DOI: 10.1158/1078-0432.CCR-19-2152 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Running Title: HDAC inhibitor and anthracycline combination, CTCL 1 Romidepsin in Combination with Liposomal Doxorubicin is Safe 2 and Effective in Patients with Relapsed or Refractory T-cell 3 Lymphoma: Results of a Translational Phase I Dose-Escalation 4 Study 5 Khoan Vu1, Chi-Heng Wu1, Chen-Yen Yang1, Aaron Zhan1, Erika Cavallone1, Wade Berry1, Pamela 6 Heeter2, Laura Pincus1, Matthew Wieduwilt3, Basem William2, Charalambos Andreadis1, Lawrence 7 Kaplan1, Frank McCormick4, Pierluigi Porcu2, Jonathan E. Brammer2*, Weiyun Z. Ai1* 8 1Division of Hematology and Blood and Marrow Transplantation, Department of Medicine, 9 University of California, San Francisco, 2Division of Hematology, James Comprehensive Cancer 10 Center, Department of Internal Medicine, The Ohio State University, Columbus, OH, 3Moores Cancer 11 Center, University of California, San Diego, 4Hellen Diller Family Cancer Center, University of 12 California, San Francisco 13 *J.E.B. and W.Z.A. contributed to the work equally 14 Correspondence: Weiyun Ai, Division of Hematology and Blood and Marrow Transplantation, University 15 of California, San Francisco, 505 Parnassus Avenue, M1286, Box 0324, San Francisco, CA 94143- 16 0324. Phone: 415-353-4061; E-mail: [email protected]. 17 18 Disclosure of Potential Conflicts of Interest: 19 K.V. owns stocks of Celgene. C.A. has received research funding and honorarium from Celgene. P.P. 20 has received research funding from Viracta, Innate Pharma, Kiowa, Daiichi, Incyte, and BeiGene, as 21 well as consulting from Innate Pharma, Viracta, and Spectrum. J.E.B. has received research funding 22 from Celgene. The remaining authors declare no competing financial interests. 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 1 Downloaded from clincancerres.aacrjournals.org on September 29, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on November 26, 2019; DOI: 10.1158/1078-0432.CCR-19-2152 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Running Title: HDAC inhibitor and anthracycline combination, CTCL 1 Abstract 2 Purpose: The histone deacetylase (HDAC) inhibitor romidepsin and the anthracycline liposomal 3 doxorubicin (LD) have modest single-agent activity in cutaneous T-cell lymphoma (CTCL) and 4 peripheral T-cell lymphoma (PTCL). We investigated the safety and efficacy of the combination of 5 these two agents in CTCL and PTCL. 6 7 Patients and Methods: Using CTCL cell lines and primary CTCL tumor cells, we demonstrated 8 synergistic anti-tumor activity with romidepsin plus doxorubicin. We then conducted a phase I dose- 9 escalation study of the romidepsin/LD combination in relapsed/refractory CTCL and PTCL. The 10 primary objective was to determine the maximum tolerated dose (MTD) of romidepsin in combination 11 with LD at 20 mg/m2 IV, once every 28 days. 12 13 Results: Eleven CTCL and 12 PTCL patients were treated. The MTD of romidepsin was determined to 14 be 12 mg/m2. Grade 3/4 hematologic toxicities included thrombocytopenia (17%), anemia (13%), and 15 neutropenia (9%). The most frequent treatment-related non-hematologic adverse events were fatigue 16 (48%), nausea (48%), vomiting (35%), and anorexia (30%). Among 21 evaluable patients, the overall 17 response rate was 70% (1 CR, 6 PR) in CTCL and 27% (3 CR, 0 PR) in PTCL. Of the CTCL patients, 18 8 of 10 had skin response, including 6 patients (60%) achieving skin involvement < 10% of their body 19 surface area at time of best response. 20 21 Conclusions: Romidepsin plus LD demonstrated an acceptable safety profile and promising clinical 22 efficacy with deep skin responses in relapsed/refractory CTCL. Thus, this combination could be 23 considered as a bridge to skin-directed treatment or allogeneic hematopoietic cell transplantation in 24 patients with aggressive CTCL. 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 2 Downloaded from clincancerres.aacrjournals.org on September 29, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on November 26, 2019; DOI: 10.1158/1078-0432.CCR-19-2152 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Running Title: HDAC inhibitor and anthracycline combination, CTCL 1 Translational Relevance 2 Based on in vitro studies showing that histone deacetylase (HDAC) inhibitors such as romidepsin 3 potentiate the activity of anthracyclines in both B-cell lymphoma and acute leukemia cell lines, we 4 tested the hypothesis that the combination of romidepsin and doxorubicin would have synergistic 5 effects against T-cell lymphoma in pre-clinical models and, by extension, in patients with 6 relapsed/refractory T-cell lymphoma. We found that romidepsin was synergistic with doxorubicin in 7 growth inhibition and apoptosis induction in both cutaneous T-cell lymphoma (CTCL) cell lines and 8 patient-derived primary CTCL cells. This led us to develop a phase I clinical trial testing romidepsin 9 combined with liposomal doxorubicin (LD) in patients with relapsed/refractory CTCL and peripheral T- 10 cell lymphoma (PTCL). Results from our trial show that this drug combination is highly active and well- 11 tolerated in CTCL leading to deep skin responses, consistent with our hypothesis. 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 3 Downloaded from clincancerres.aacrjournals.org on September 29, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on November 26, 2019; DOI: 10.1158/1078-0432.CCR-19-2152 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Running Title: HDAC inhibitor and anthracycline combination, CTCL 1 Introduction 2 Cutaneous T-cell lymphoma (CTCL) is a rare non-Hodgkin lymphoma that principally involves the skin 3 and, in advanced stages, the lymph nodes, peripheral blood, and visceral organs. Mycosis fungoides 4 (MF) is the most common subtype of CTCL, comprises 50% of all CTCLs.1 Sézary syndrome (SS) is a 5 leukemic form of CTCL, characterized by diffuse erythroderma and circulating neoplastic T-cells in the 6 blood. While patients with early stage disease generally have a good prognosis, patients with relapsed 7 or advanced stage (IIB to IVB) MF or SS, have a median overall survival (OS) of 4-5 years, a result that 8 has not improved in over four decades.2–4 These patients frequently require systemic therapy; 9 however, complete response (CR) rates are low, and response durations are typically short. Thus, 10 there is an urgent need for systemic therapies that improve response rates, duration of response, and 11 OS in relapsed and advanced stage CTCL. 12 13 Peripheral T-cell lymphoma (PTCL) represents 10-15% of all non-Hodgkin lymphoma cases.5 PTCL is a 14 heterogeneous disease with over twenty subtypes with different morphologies and clinical features. 15 Clinical outcomes in PTCL, particularly in patients with relapsed/refractory disease, remain poor with a 16 median OS after relapse of 5.5 months.6 Multiple agents, including pralatrexate and romidepsin, have 17 been approved by the U.S. Food and Drug Administration for relapsed/refractory PTCL and have 18 modest response rates ranging from 20-30%.7–9 Thus, there is a critical need for novel therapies and 19 drug combinations that are highly effective and tolerable for patients with relapsed/refractory PTCL. 20 21 Histone deacetylase (HDAC) inhibitors have been shown to be clinically active in both CTCL and PTCL 22 as hyper-acetylation is a recurrent aberrancy in T-cell lymphomas.7,9–16 Romidepsin is a unique 23 bicyclic, class 1, selective HDAC inhibitor that has demonstrated efficacy in CTCL and PTCL.10,16 In a 24 phase II trial in relapsed/refractory CTCL, romidepsin demonstrated an ORR of 34%, including 6% of 25 patients with CR.16 A subsequent phase II trial of romidepsin in relapsed/refractory CTCL incorporating 26 the more stringent 2011 International Society for Cutaneous Lymphomas (ISCL) consensus response 27 criteria, the global ORR was 34% with a skin response of 38 – 41%.17 In a pivotal phase II trial in 28 relapsed/refractory PTCL, romidepsin demonstrated an overall response rate (ORR) of 25%, including 29 a 15% rate of CR or unconfirmed complete response (Cru).10 The results led to FDA approval for 30 romidepsin for the treatment of relapsed/refractory CTCL and PTCL. 31 32 Liposomal doxorubicin (LD) is an effective chemotherapeutic option for patients with CTCL. The 33 EORTC 21012 multicenter phase II study of LD 20 mg/m2 IV given every 2 weeks demonstrated a 34 global ORR of 41% (20/49) with a CR rate of 6% and a skin response of 60.5%.18 Subsequently, a 35 phase II trial of LD 20 mg/m2 every 2 weeks for 8 cycles followed by bexarotene reported an ORR of 36 41% at 16 weeks.19 LD has also been evaluated in patients with TCL, including PTCL, in combination 37 with gemcitabine with modest results.20 38 39 Romidepsin and LD have demonstrated modest effectiveness in patients with relapsed and refractory 40 CTCL and PTCL. However, there is a critical need to identify novel combinations to more effectively 41 treat these aggressive diseases. In vitro studies have shown that HDAC inhibitors such as romidepsin 42 potentiate the cytotoxic effects of anthracyclines in both B-cell lymphoma and acute myeloid leukemia 43 cell lines.21–23 However, whether the combination of an HDAC inhibitor and anthracycline has 44 augmented activity in mature T-cell lymphoma is unknown.