PILOT PHASE II STUDY OF SELINEXOR IN COMBINATION WITH IFOSFAMIDE, ETOPOSIDE AND DEXAMETHASONE IN PATIENTS WITH RELAPSED OR REFRACTORY PERIPHERAL T‐CELL LYMPHOMAS (R/R PTCLS)

Abstract

Introduction: The prognosis of R/R PTCLs is very poor. Selinexor is an oral, first in class, potent selective inhibitor of nuclear exportin, that shown promising overall response rate (ORR) and complete response (CR) in a phase I study of selinexor in combination with high-dose dexamethasone, ifosfamide, carboplatin and etoposide in R/R PTCLs, Tang et al (Haematologica 2021). These results are very preliminary and need to be confirmed; for this reason, we designed the PTCL S-IDE study (EudraCT number 2021-006229-23). Methods: S-IDE is a phase II multicenter pilot study of Selinexor in combination with Ifosfamide, Etoposide and Dexamethasone in patients with R/R PTCLs. We decided to omit carboplatin in order to reduce nausea and hematologic toxicity, in addition the activity of carboplatin in PTCL is uncertain. Key inclusion criteria are: age 18–75 years, R/R histologically confirmed PTCL (PTCL-NOS, angioimmunoblastic T cell lymphoma - AITL, anaplastic large cell ALK negative—ALK neg, T-helper follicular—TFH) after at least one course of anthracycline containing regimen chemotherapy (including or not high dose chemotherapy and stem cell transplantation - SCT), PS ECOG ≤2, adequate organ function. All patients will receive intravenous S-IDE on a 21-day cycle: Selinexor (40 mg on day 3, 5 and 7); Ifosfamide 5 g/mq on day 2; Etoposide 100 mg/mq on days 1–3; Dexamethasone 20 mg/day on days 3–7. Patient in CR at the end of the 4 courses receive a maintenance with selinexor (selinexor 60 mg weekly, until progression or unacceptable toxicity) or proceed to allo-SCT or auto-SCT according to donor availability, patient age and comorbidities. The primary endpoint is ORR at the end of 4 courses of S-IDE; the secondary endpoints are duration of response, 18-months PFS and OS, treatment related mortality, CR by histotypes, rate of patients able to undergo SCT, and adverse events. Exploratory biological analyses are ORR in subgroups based on GATA3 and TBX21 expression; loss of tumor suppressor genes on the CDKN2A/B-TP3 axis and PTEN-PI3K pathways as well as genetic gains and amplification of STAT3 and MYC; the presence of mutations described as associated with a poor prognosis, including CD28 mutations in AITL; TP63 rearrangement, loss of TP53, and loss of PRDM1 in ALK− ALCL; GATA3 , TP53, and/or CDKN2A in ALK− ALCL; and alterations in histone methyltransferase genes KMT2A, KMT2B, or KDM6A and FAT1 in PTCL-NOS; XPO1 expression; circulating tumor DNA (ctDNA). The sample size is 30 patients, with enrollment 18 months in 9 Italian centers. The sample size calculation refers to the primary endpoint; a sample size of 30 patients will allow to achieve a statistical power of more than 90% (94%) to test an increase of 30% of ORR (from 50% under null hypothesis to 80% under the alternative one) using a two-sided one sample binomial test with alpha =5%. The accrual is ongoing; at the end of February 2023, 2 patients have been enrolled. Keywords: aggressive T-cell non-Hodgkin lymphoma, combination therapies, ongoing trials Conflicts of interests pertinent to the abstract. A. Chiappella Consultant or advisory role Celgene-BMS, Gilead-Sciences, Ideogen, Janssen, Roche, SecuraBIO, Takeda Other remuneration: Lecture fees/Educational activities: Astrazeneca, Celgene-BMS, Gilead-Sciences, Incyte, Janssen-Cilag, Novartis, Roche, Takeda