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Phase I Study of Selinexor in Combination With Phase I study of selinexor in combination with dexamethasone, ifosfamide, carboplatin, etoposide chemotherapy in patients with relapsed or refractory peripheral T-cell or natural-killer/T-cell lymphoma by Tiffany Tang, Peter Martin, Nagavalli Somasundaram, Cindy Lim, Miriam Tao, Eileen Poon, Maica J.D. Yunon, Shu Q. Toh, Sean X. Yan, Mohamad Farid, Jason Y. Chan, and Soon T. Lim Haematologica 2020 [Epub ahead of print] Citation: Tiffany Tang, Peter Martin, Nagavalli Somasundaram, Cindy Lim, Miriam Tao, Eileen Poon, Maica J.D. Yunon, Shu Q. Toh, Sean X. Yan, Mohamad Farid, Jason Y. Chan, and Soon T. Lim. Phase I study of selinexor in combination with dexamethasone, ifosfamide, carboplatin, etoposide chemotherapy in patients with relapsed or refractory peripheral T-cell or natural-killer/T-cell lymphoma. Haematologica. 2020; 105:xxx doi:10.3324/haematol.2020.251454 Publisher's Disclaimer. E-publishing ahead of print is increasingly important for the rapid dissemination of science. Haematologica is, therefore, E-publishing PDF files of an early version of manuscripts that have completed a regular peer review and have been accepted for publication. E-publishing of this PDF file has been approved by the authors. After having E-published Ahead of Print, manuscripts will then undergo technical and English editing, typesetting, proof correction and be presented for the authors' final approval; the final version of the manuscript will then appear in print on a regular issue of the journal. All legal disclaimers that apply to the journal also pertain to this production process. Article type: Original Article Title: Phase I study of selinexor in combination with dexamethasone, ifosfamide, carboplatin, etoposide chemotherapy in patients with relapsed or refractory peripheral T-cell or natural- killer/T-cell lymphoma. Authors and Affiiations: Tiffany Tang*1, Peter Martin2, Nagavalli Somasundaram1, Cindy Lim3, Miriam Tao1, Eileen Poon1, Maica JD. Yunon3, Shu Q. Toh3, Sean X Yan4, Mohamad Farid1, Jason Y. Chan1, and Soon T. Lim1 1. Division of Medical Oncology, National Cancer Centre Singapore, Singapore 2. Division of Medicine, Weill Cornell Medical College, New York, USA 3. Division of Clinical Trials and Epidemiology, National Cancer Centre Singapore, Singapore 4. Department of Nuclear Medicine and Molecular Imaging, Singapore General Hospital, Singapore Running head: Phase I study of selinexor-DICE in relapsed PTCL and NKTL *Corresponding author Name: Dr Tiffany Tang Affiliation: Division of Medical Oncology, National Cancer Centre Singapore Address: 11 Hospital Crescent, Singapore 169610 Telephone: (65) 6436800 Email: [email protected] Article summary: 1) The aim of the study was to determine the safety and maximum tolerated dose (MTD) of selinexor when combined with dexamethasone, ifosfamide, carboplatin, etoposide (DICE) in relapsed or refractory T-cell and natural-killer/T-cell lymphoma 2) The MTD for Selinexor was 40mg when combined with DICE. The combination had promising CR rates but poor tolerability in patients with R/R TCL and NKTL. Abstract Selinexor is a selective inhibitor of nuclear export with anti-cancer properties. We performed a phase I study to determine the safety and maximum tolerated dose (MTD) of selinexor when combined with high-dose dexamethasone, ifosfamide, carboplatin and etoposide (DICE) in relapsed/refractory (R/R) T-cell lymphoma (TCL) and natural-killer/T-cell lymphoma (NKTL). Patients with R/R TCL and NKTL were treated with standard dose ICE, dexamethasone 20mg on days 3 to 7, and escalating doses of oral selinexor on days 3, 5 and 7 in a 3+3 design. Dose level (DL) 1, 2 and 3 were 40, 60 and 80mg respectively. Eleven patients with a median age of 60 were enrolled; 6 at DL1 and 5 at DL2. Patients had received a median of 2 (range 1-4) prior lines of treatment and 7 had primary refractory disease at study entry. Patients received a median of 3 cycles (range 1-6) of selinexor-DICE. The most common grade (G) 1/2 toxicities included nausea (64%), fatigue (55%), and anorexia (45%) and the most common G 3/4 toxicities included thrombocytopenia (82%), anemia (82%), neutropenia (73%), and hyponatremia (73%). Two patients developed dose- limiting toxicities at DL2 and one at DL1. Five patients discontinued treatment for reasons other than disease progression or lack of response. Of the 10 evaluable patients, the overall and complete response rates were 91% and 82% respectively. The MTD of selinexor was 40mg when combined with DICE. The combination showed promising CR rates in patients with R/R TCL and NKTL but was poorly tolerated. (clinicaltrials.gov identifier: NCT03212937) Acknowledgements: The authors would like to thank the National Medical Research Council (Singapore) Clinical Trials Grants (NMRC/CTGICT/0001/2017) and Karyopharm Therapeutics for funding this study. The protocol development was supported by the American Society of Hematology, Clinical Research Training Institute (2015). Contributions: TT and PM developed the trial concept. TT, NS, MT, EP, MF, JYC, STL were involved in recruiting and managing the patients on trial. CL performed the statistical analyses for the study. SXY evaluated all the scans to ascertain the response assessments. MJDY and SQT were the clinical trial coordinators involved in the data collection and running of the study. TT, PM and STL supervised the conduct of the study. All the authors reviewed the final manuscript. Key Words: Aggressive Non-Hodgkin lymphoma, lymphoproliferative disorders Manuscript Introduction: T-cell lymphoma (TCL) is a heterogenous group of non-Hodgkin lymphomas (NHL) seen more commonly in Asia compared to the West.(1, 2) The 5-year overall survival rates are approximately 30% for the most common subtypes of TCL, including peripheral-T cell lymphoma (PTCL)-not otherwise specified (NOS), angioimmunoblastic T-cell lymphoma (AITL) and natural-killer/T-cell lymphoma (NKTL).(2) PTCL patients who relapse or progress after initial therapy have poor survival outcomes with median progression-free (PFS) and overall survival (OS) of 3.1 and 5.5months respectively.(3) However, patients who achieve a complete response (CR) to salvage therapy have better median PFS and OS (12.2 and 18months respectively).(3) Some patients who achieve CR to salvage therapy may be considered for high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT) consolidation with curative intent.(4) Thus there is a need to improve CR rates for salvage regimens. Exportin 1 (XPO1/CRM1) is a nuclear export protein that is responsible for the nuclear to cytoplasmic translocation of tumor suppressor proteins (TSP) and growth regulator proteins (GRP) such as TP53, p21, p27, FOXO3 and nucleophosmin 1 (NPM1), leading to their inactivation.(5) XPO1 is overexpressed in many malignancies including TCL and increased XPO1 expression is associated with a poor survival.(6-10) XPO1 also transports topoisomerase II enzymes to the cytoplasm and cytoplasmic localization of topoisomerase II enzymes have been identified as a mechanism of cancer resistance. Therefore when topoisomerase IIα enzymes are not in contact with DNA, topoisomerase II inhibitors, such as doxorubicin, are unable to induce cell death.(11) Selinexor® is an oral, first in class, potent selective inhibitor of nuclear export (SINE), which bind to XPO1, leading to nuclear retention of the TSP, GRP, and topoisomerase IIα enzymes, restoring their function. Selinexor has received Food and Drug Administration (FDA) approval for relapsed or refractory multiple myeloma and diffuse large B-cell lymphoma, and has shown significant anti-cancer activity across a range of pre-clinical models of cancer, including T- acute lymphoblastic leukemia (T-ALL).(12) There were also preclinical studies demonstrating the ability of selinexor to sensitize cancer cells to topoisomerase inhibitors,(13) alkylating agents(5) and steroids.(14) A phase I study of selinexor in relapsed/refractory NHL showed overall response rates (ORR) of about 30%.(15) We hypothesized that selinexor could synergize with ifosfamide (alkylating agent) and etoposide (topoisomerase II inhibitor) in the ifosfamide, carboplatin and etoposide (ICE) regimen and we added high-dose dexamethasone to this regimen to improve the efficacy of ICE as a salvage regimen for TCL. We conducted a phase I study to identify the dose of selinexor that could be combined safely with standard-dose ICE and high-dose dexamethasone (DICE) in relapsed or refractory TCL (clinicaltrials.gov identifier: NCT03212937). Methods: Patients Recruited patients had histologically confirmed relapsed or refractory PTCL or NKTL. Patients with CD30+ anaplastic large cell lymphoma (ALCL) must have failed treatment with brentuximab vedotin. The study was conducted at the National Cancer Centre Singapore (NCCS) and the Singapore General Hospital (SGH) after approval by the Singhealth Institutional Review Board (IRB) and in accordance with the Declaration of Helsinki and Good Clinical Practice Guidelines of the International Conference on Harmonization. Written consent was obtained from all patients prior to study entry. Study design This was an open-label, phase I study where eligible patients were treated with ICE plus escalating doses of oral selinexor in a 3+3 design. The primary objective was to assess the safety and determine the maximum tolerated dose (MTD) of selinexor that could be combined with standard dose ICE. Dose level 1 of selinexor was chosen as 40mg because at the time of study development, the recommended phase II dose of selinexor from phase I studies was 60mg (fixed dose)(15, 16) and there was the concern that Asian patients tolerated selinexor poorer than the Caucasian patients. Hence dose levels (DL) -1, 1, 2 and 3 were 20, 40, 60 and 80mg respectively. All patients received intravenous doses of ICE on a 21-day cycle: Ifosfamide 5g/m2 over days 1-3, carboplatin AUC 5 on day 1 and etoposide 100mg/m2 on days 1-3. Selinexor was administered on days 3, 5 and 7. Additionally, all patients received oral dexamethasone 20mg/day for 5 days on days 3-7 for anticipated anti-cancer synergy of steroids with selinexor.
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