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Phase I study of selinexor-DICE in relapsed PTCL and NKTL
transplantation (SCT) consolidation with curative intent.4 Thus there is a need to improve complete response rates for salvage regimens.
Exportin 1 (XPO1/CRM1) is a nuclear export protein that is responsible for the nuclear to cytoplasmic translo- cation of tumor suppressor proteins (TSP) and growth reg- ulator 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 poor survival.6-10 XPO1 also transports topoisomerase II enzymes to the cytoplasm and cytoplasmic localization of topoisomerase II enzymes has been identified as a mech- anism of cancer resistance. Therefore, when topoiso- merase IIα enzymes are not in contact with DNA, topoi- somerase 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, which binds to XPO1, leading to nuclear retention of the TSP, GRP, and topoisomerase IIα enzymes, restoring their function.
Selinexor has received Food and Drug Administration approval for relapsed or refractory multiple myeloma and diffuse large B-cell lymphoma, and has shown significant anticancer activity across a range of preclinical models of cancer, including T-cell acute lymphoblastic leukemia.12 There were also preclinical studies demonstrating the abil- ity of selinexor to sensitize cancer cells to topoisomerase inhibitors,13 alkylating agents5 and steroids.14 A phase I study of selinexor in relapsed/refractory non-Hodgkin lymphomas showed overall response rates of about 30%.15 We hypothesized that selinexor could synergize with ifosfamide (an alkylating agent) and etoposide (a topoisomerase II inhibitor) in the ifosfamide, carboplatin and etoposide (ICE) regimen and we added high-dose dex- amethasone 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 com- bined safely with standard-dose ICE and high-dose dex- amethasone (DICE) in relapsed or refractory TCL (clinical- trials.gov identifier: NCT03212937).
Methods
Patients
Recruited patients had histologically confirmed relapsed or refractory PTCL or NKTL. Patients with CD30+ anaplastic large cell lymphoma (ALCL) had to have failed treatment with brentux- imab vedotin. The study was conducted at the National Cancer Center Singapore and the Singapore General Hospital after approval by the Singhealth Institutional Review Board 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 their entry into the study.
Study design
This was an open-label, phase I study in which eligible patients were treated with DICE 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 of selinexor that could be combined with DICE.
The first dose level (DL) of selinexor was chosen as 40 mg because at the time of developing the study the recommended phase II dose of selinexor from phase I studies was 60 mg (fixed
dose)15,16 and there was concern that Asian patients tolerated selinexor less well than Caucasian patients. Hence DL -1, 1, 2 and 3 were 20, 40, 60 and 80 mg, respectively.
All patients received intravenous doses of ICE in a 21-day cycle: ifosfamide 5 g/m2 over days 1-3, carboplatin (area under the curve 5) on day 1 and etoposide 100 mg/m2 on days 1-3. Selinexor was administered on days 3, 5 and 7. Additionally, all patients received oral dexamethasone 20 mg/day for 5 days on days 3-7 for antici- pated anticancer synergy of steroids with selinexor. Anti-emetics included oral aprepitant and granisetron 3 mg on days 1-3 and dexamethasone 8 mg on days 1-2. Oral olanzapine 5 mg was rec- ommended with each dose of selinexor.
Eligible patients could undergo HDC and SCT after at least two cycles of study treatment. Patients who were not eligible for SCT could receive up to six cycles of the study treatment. Patients could also receive maintenance selinexor (60 mg weekly) if they had not progressed upon completion of selinexor-DICE.
Assessment of adverse events and dose-limiting toxicities
Dose-limiting toxicities were defined as any of the following treatment-related toxicities occurring during the first cycle of treat- ment: failure to resolve any grade 3 or higher non-hematologic toxicities, platelet count of less than 75x109/L or absolute neu- trophil count of less than 1x109/L by day 29, a platelet count of less than 25x109/L or an absolute neutrophil count of less than 0.5x109/L lasting more than 14 days, a platelet nadir of 10x109/L or less, or any grade 5 toxicities.
Response assessment
Responses were assessed using the revised International Working Group Criteria for non-Hodgkin lymphoma.17 Tumor measurements with positron emission tomography and computed tomography scans were performed at baseline, after two cycles of selinexor-DICE, and 6-8 weeks after the last cycles of selinexor- DICE or after HDC/SCT.
Statistical analysis
Any patient who received one dose of selinexor was included in the safety population and only the patients who completed two cycles of treatment and the first response assessment were includ- ed in the efficacy analysis.
Results
Eleven patients were recruited into the study. The medi- an age was 60 years (range, 34-74), and nine were male. All patients were Asian; seven (64%) were Chinese, two (18%) were Malay, one (9%) was Indian and another (9%) was Myanmarese. The most common histological subtype in this study was AITL (n=5), followed by PTCL-NOS (n=2). There were one of each of the following histological subtypes; ALK-negative ALCL, ALK-positive ALCL, NKTL and PTCL with T-follicular helper phenotype. Two patients had stage II disease and the rest had stage IV dis- ease at study entry. The patients had received a median of two prior lines of treatment, one had received prior HDC and autologous SCT, and one had been previously admin- istered radiotherapy. Seven patients (64%) had primary refractory disease, defined as disease that had not respond- ed to any prior chemotherapy, or disease that progressed within 8 weeks from the end of treatment response assess- ment. All patients had an Eastern Cooperative Oncology Group performance status of 0 or 1. (Table 1)
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