Inhibitor Of Nuclear Export Selinexor Research Articles

Preliminary Safety and Efficacy of Venetoclax and Selinexor in Combination with Chemotherapy in Pediatric and Young Adult Patients with Relapsed or Refractory Acute Myeloid Leukemia: Selclax

Background: Survival rates for children and adolescent/young adults (AYAs) with relapsed or refractory acute myeloid leukemia (R/R AML) remain poor. Previous clinical trials have demonstrated that the selective inhibitor of nuclear export selinexor and the BCL2 inhibitor venetoclax are each safe and active when combined with chemotherapy in children with R/R AML (NCT02212561, NCT03194932). However, many patients are refractory to these combinations. Preclinical data indicate that selinexor and venetoclax are synergistic and that selinexor may abrogate resistance to venetoclax. We thus aimed to characterize the toxicity profile and explore preliminary activity of venetoclax and selinexor with chemotherapy in pediatric and AYA patients with R/R AML and report results from the dose escalation phase of the SELCLAX clinical trial (NCT04898894). Methods: SELCLAX is a Phase I and expansion cohort study of selinexor and venetoclax in combination with chemotherapy in pediatric and AYA patients with R/R AML. For the dose escalation phase, eligibility criteria included < 30 years of age, adequate organ function and performance status, primary refractory, early first relapse (< 12 months from initial diagnosis), relapsed and refractory to salvage, post-transplant relapse or second or greater relapse AML or acute leukemia of ambiguous lineage (ALAL). The primary endpoint was determination of the recommended phase 2 dose (RP2D) of venetoclax and selinexor with chemotherapy. In the dose level 1 (DL1) cohort, venetoclax was given at 360 mg/m 2 per dose (max 600 mg) on days 1-21 in combination with selinexor at 40 mg/m 2 on days 1, 8, 15. For dose level 2 (DL2), venetoclax was dosed as in DL1, and selinexor was dosed at 40 mg/m 2 twice weekly on days 1, 3, 8, 10, 15, 17. Chemotherapy (fludarabine 30 mg/m 2, cytarabine 2 g/m 2 ± granulocyte colony stimulating factor 5 mcg/kg [FLA(G)]) was given on days 16-20. Response was evaluated by blast percentage in day 8 and 15 peripheral blood and in day 15 and end-cycle bone marrow. Any patient with a two-log (100-fold) reduction in measurable residual disease (MRD) between baseline and Day 15 was designated an “exceptional responder” (ER). At the discretion of the treating physician, ER patients could continue venetoclax until day 28 with additional selinexor (DL1: day 22; DL2: day 22, 24); FLA(G) could either be omitted or given on days 30-34; omission of FLA(G) deemed a patient non-evaluable (NE) for dose-limiting toxicity (DLT). Evaluable patients were assessed for DLTs, and dosing was escalated according to a rolling-six design. Results: As of July 14, 2023, fifteen patients (aged 3-17 years) with R/R AML (n=14) or ALAL (n=1) were enrolled in the dose escalation phase ( Table 1). Nearly all patients had high-risk cytomolecular features: KMT2A-rearranged (n=5), NUP98-rearranged (n=5), -7/del(7) (n=3), or FUS::ERG (n=1). Seven patients were enrolled on DL1 (one NE, replaced); eight patients were enrolled on DL2 (two NE, replaced). In the DL1 cohort, one DLT was reported of grade 3 anorexia requiring nasogastric feeds; however, this was cofounded by a prior history of anorexia, mucositis, and poor dentition requiring extractions and restorations. At DL2, one patient experienced a hematologic DLT with failure to recover absolute neutrophil count above 500/uL and platelet count above 25,000/uL by day 43 from start of FLA(G). There were no DLTs in the other five evaluable patients in DL2 and no serious adverse events (AEs) reported. The most common Grade 3 or 4 AE was febrile neutropenia (16.7%). Of the evaluable patients, five of twelve (41.7%) achieved complete response (CR) or complete response with incomplete count recovery (CRi). One patient was an ER on Day 15 at DL2 and did not receive FLA(G); thus, this patient was not evaluable for DLT assessment. Six patients proceeded to hematopoietic cell transplant after protocol therapy, five of whom are alive to date. Conclusion: Venetoclax and selinexor with FLA(G) chemotherapy is a tolerable combination in pediatric and AYA patients with R/R AML. Early activity of this combination regimen was observed in some patients, including those with primary refractory or early first-relapsed AML. Enrollment of the dose expansion phase at DL2 is underway in two cohorts: venetoclax-naïve and venetoclax-exposed.

Current status and future prospects of diffuse large B-cell lymphoma treatment

R-CHOP therapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) has been used as the standard treatment regimen for patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL), since the introduction of rituximab in the early 2000s. Recently, polatuzumab vedotin and anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapy have been introduced as potential treatment options for relapsed or refractory DLBCL. The effectiveness of polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisone for newly diagnosed CD20-positive DLBCL, except for the low-risk group of the international prognostic index, was reported in 2022. Bispecific antibodies such as epcoritamab, mosunetuzumab, and glofitamab, anti-CD19 antibody drug tafasitamab combined with lenalidomide, CD19 antibody drug conjugate loncastuximab tesirine, oral selective inhibitor of nuclear export selinexor, and several new agents have been investigated for DLBCL. For non-germinal center B-cell type DLBCL, R-CHOP combined with acalabrutinib is being evaluated. This review summarizes the current standard of care for DLBCL and outlines the recently introduced therapeutic agents or those that are under development in Japan.

Selinexor Is an Effective Cancer Treatment in Hypoxic Conditions and Synergizes with Proteasome Inhibitors to Treat Drug Resistant Multiple Myeloma

Introduction: Multiple myeloma (MM) is a plasma cell malignancy, characterized by plasma cell accumulation in the bone marrow (BM) associated with lytic bone disease. Despite the implementation of novel therapies, more than 70% of MM patients relapse due to drug resistance. Low oxygenation (hypoxia) in the BM microenvironment, which was shown to decrease beyond physiologic BM conditions during the progression of MM, together with cellular and acellular components, plays a critical role in drug resistance. Increased levels of the nuclear exporter of tumor suppressors, exportin 1 (XPO1), was demonstrated in MM, and XPO1 inhibition showed a broad anti-tumor activity. In this study, we tested inhibition of XPO1 using the novel oral, covalent, slowly reversible inhibitor of nuclear export selinexor currently in Phase I/II clinical trials on sensitizing the hypoxia-inducible drug resistant MM cells both in vitro and in vivo.Methods: MM cell lines (MM1s, H929, OPM2 and U266) were treated with increasing concentrations of selinexor in normoxic (21% O2) and hypoxic (1% O2) conditions with or w/o bortezomib or carfilzomib. Assays included MTT proliferation Annexin V/PI staining for apoptosis, PI staining and immuniblots for cell cycle analysis.We tested the effects of selinexor as a single agent on tumor initiation in vivo, where MM1s-Luc-GFP cells were injected intravenously (IV) into SCID mice and mice were treated instantaneously with selinexor (15mg/kg) or vehicle (PVP + F-68) three times a week. We also tested the effect of selinexor (15mg/kg) as a single agent on tumor progression and survival in mice with established MM tumor. Furthermore, we studied the effects of selinexor on sensitization to bortezomib-resistant MM cells in vivo. MM1s-Luc-GFP cells were injected IV into SCID mice and tumors were allowed to grow for three weeks. Animals were then treated with a high-dose of bortezomib (1.5mg/kg twice a week) for two weeks to induce resistance to bortezomib. The mice were then randomly divided into 3 groups treated with (1) bortezomib (0.5mg/kg), (2) KPT-330 (10mg/kg), and (3) a combination of selinexor and bortezomib. Selinexor was administered by oral gavage three times a week (days 1, 3 and 5) and bortezomib was injected intraperitoneally twice a week (days 1 and 4). Tumor progression was imaged using bioluminescence imaging (BLI).Results: Selinexor, as a single agent, decreased proliferation, induced G1 cell cycle arrest and increased apoptosis of MM cells in both hypoxia and normoxia in a dose-dependent manner. Moreover, we found that the combination of selinexor with bortezomib or carfilzomib reversed the hypoxia-induced resistance in MM cells to proteasome inhibition and induced a synergistic effect on the inhibition of cell proliferation, G1 arrest and apoptosis, which was confirmed by response of respective cell signaling pathways as PI3K, MAPK and JNK.In vivo studies revealed that selinexor alone delayed tumor initiation and decreased by half existing tumor size as a single agent (p=0.0397), and significantly extended mice survival (53 days on vehicle versus 62 days on selinexor, p=000375). In addition, MM-bearing mice which developed resistance to bortezomib were resensitized by treatment of selinexor combined with bortezomib, decreasing tumor burden and showed considerably extended survival (half of the mice were alive at day 52) compared to mice treated with either selinexor (half of the mice were alive at day 49) or bortezomib alone (half of the mice were alive at day 40) (bortezomib versus selinexor p=0.0014, bortezomib versus combination treatment p=0.0004 as analyzed by Student t-test).Conclusions: The orally available inhibitor of nuclear export, selinexor, decreased survival of MM cells in vitro and delayed tumor initiation and tumor progression in vivo as a single agent. In addition, selinexor overcame hypoxia-induced resistance to proteasome inhibitors and resensitized MM cells to therapy both in vitro and in vivo, extending mice survival. These data provide a basis for future clinical trials to sensitize relapsed/refractory MM patients to therapy by inhibition of XPO1 with selinexor as well as combination studies of selinexor and proteasome inhibitors. A study of selinexor and carfilzomib is currently ongoing and early results that were published last year showed marked activity for this combination treatment in heavily pretreated MM patients. DisclosuresLandesman:Karyopharm: Employment. Azab:Karyopharm: Research Funding; Selexys: Research Funding; Verastem: Research Funding; Targeted Therapeutics LLC: Other: Founder and owner ; Cell Works: Research Funding.

Safety and antitumor activity of selinexor (KPT-330), a first-in-class, oral XPO1 selective inhibitor of nuclear export: A phase I study expanded with colon cancer cohort.

482 Background: Tumor suppressor proteins (TSPs) are inactivated by their export from the nucleus by Exportin1 (XPO1/CRM1). The oral selective inhibitor of nuclear export selinexor (KPT-330)restores the nuclear localization and function of TSPs and shows a broad anti-tumor activity in animal models. Here we report on the treatment of a subset of patients (pts) with metastatic colorectal cancer (CRC) in a phase I trial of selinexor. Methods: Objectives were to determine the recommended phase 2 dose, evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), and tumor response (RECIST 1.1) of selinexor administered in two different schedules with 8 or 10 doses in a 28-day cycle. An expansion cohort of 15 pts with CRC was planned. Results: Twenty-seven pts with CRC were treated across eight doses (3-40 mg/m2) including 15 pts in the expansion cohort (30-35 mg/m2). Median age was 61 yrs and median number of prior regimens was 4. MTD of the 10-dose schedule was 30 mg/m2. MTD for the 8-dose schedule has not been reached. Thirteen pts experienced drug related gr 3-4 adverse events (AEs) including fatigue (n = 6), hyponatremia (n = 5), thrombocytopenia (n = 3), anorexia (n = 3), dehydration (n = 2), anemia (n = 2), hyperglycemia (n = 1), pulmonary embolism (n = 1), and hypotension (n = 1). The most common gr 1-2 drug related AEs were nausea (74 %), anorexia (67 %), fatigue (67 %), vomiting (59 %), dysgeusia (52 %), and weight loss (48 %). Cmax increased with dose to ≈ 1.4 µM with T½ of 4.0 – 7.4 hrs. Significant increases (2-20x) in PD marker XPO1 mRNA in circulating leukocytes were observed at all doses. Analysis of tumor biopsies confirmed nuclear localization of TSPs and induction of apoptosis following selinexor. CEA decreased in 4 of 12 pts. One pt had a partial response at 23 mg/m2, 6 patients had stable disease ≥8 weeks, and 3 patients had stable disease ≥24 weeks in 25 evaluable pts Conclusions: Preliminary signals of antitumor activity in CRC pts were observed. Selinexor is generally well tolerated and prolonged drug exposure is feasible. Selinexor induces Exportin in leucocytes and apoptosis in tumor biopsies with restoration of the nuclear location of TSPs. Clinical trial information: NCT01607905.