A phase 1 clinical trial of oral eltanexor in patients with relapsed or refractory multiple myeloma

Abstract

Exportin 1 (XPO1) is the major nuclear export protein for tumor suppressor proteins (TSPs; e.g., TP53, CDKN1A, FOXO1), cell cycle regulators (e.g., CDKN1A, CDKN1B, TOB1), and eIF4E-bound oncoprotein mRNAs (e.g., MYC, BCL2L1, MDM2, CCND1).1 XPO1 is overexpressed in many malignancies, including multiple myeloma (MM), giving cancer cells a growth and survival advantage through enhanced nuclear export of TSPs and oncoprotein mRNAs. Therefore, selective inhibitors of nuclear export (SINE) compounds, which target XPO1, offer a novel approach to the treatment of MM.2 Eltanexor (KPT-8602) is an oral second-generation SINE compound currently in development for the treatment of hematological and solid tumor malignancies. Similar to other SINE compounds, eltanexor covalently binds to a critical cysteine residue (Cys528) in the cargo binding groove of XPO1 and inhibits XPO1-mediated nuclear transport.3 This leads to nuclear accumulation of multiple TSPs and reduction in oncoprotein translation, resulting in cell cycle arrest and apoptosis of cancer cells.3 In preclinical animal models, eltanexor demonstrated markedly reduced penetration across the blood–brain barrier (about 30-fold) and less weight loss, compared to the first-generation compound selinexor, allowing for more frequent dosing.3 Furthermore, eltanexor treatment (15 mg/kg given once daily for 5 days per week [QDx5]) caused 97% inhibition of tumor growth in preclinical mice models of MM (Karyopharm unpublished results). Finally, the strong synergy between eltanexor and dexamethasone antitumor activity observed in preclinical models of acute lymphoblastic leukemia,4 supports the addition of low dose of dexamethasone to eltanexor for the treatment of MM; similar strong synergy has been observed in both preclinical and clinical settings with the approved oral XPO1 inhibitor selinexor in MM.5 We therefore conducted a phase 1 study to evaluate the safety, tolerability, and efficacy of eltanexor with or without dexamethasone in patients with relapsed refractory MM (RRMM). Thirty-nine patients were enrolled between January 2016 and August 2017. Baseline characteristics at screening are listed in Table S1. Patients had received a median of seven lines of prior therapy (range 2–14) and 49% (n = 19) had penta-exposed, triple-class refractory myeloma. The median duration of study treatment exposure was 2.7 months (range 0–45.9 months). Twenty-two (56%) patients had discontinued due to progressive disease (PD), nine for an adverse event (AE), three for physician's decision, and five for patient's decision. Eltanexor was tested at six dose levels (5, 10, 20, 30, and 40 mg all given QDx5, and 60 mg [days 1, 3, 5 of each week] during 28-day cycles) utilizing a 3 + 3 study design (Table S2). Of the first three patients enrolled into the 40 mg dose level, one experienced a dose-limiting toxicity (DLT; > 4 missed doses in the first cycle as a result of nausea, vomiting, and anorexia—all grade 2 [G2]) and one experienced drug delay due to a treatment-related G3 anemia that was followed by PD and end of treatment. Three additional patients were enrolled at this dose level with none experiencing a DLT, but one withdrew consent after 22 days on study due to G2 fatigue and G1 thrombocytopenia. A cohort of patients treated at 60 mg was then enrolled to test a less frequent dose schedule and reduced cumulative dose of eltanexor. Of the four patients in this cohort, one was removed from the study after only one dose of eltanexor due to syncope requiring hospitalization, and each of the remaining three required a dose reduction. Though maximum tolerated dose (MTD) was not reached, based on these safety data the treating physicians and study sponsor agreed that dose escalation would be halted, and patients would be enrolled into two expansion cohorts to test 20 mg (n = 5) and 30 mg (n = 10) eltanexor plus dexamethasone from cycle 1 day 1 (C1D1). One DLT was observed in the 30 mg expansion cohort for G4 thrombocytopenia. In addition, although the small number of patients in these cohorts precluded a formal statistical comparison, patients in the 20 mg expansion cohort appeared to have fewer toxicities than those in the 30 mg expansion cohort (e.g. G4 thrombocytopenia 0% versus 50%, G3 neutropenia 20% versus 30%, and G3 anemia 20% versus 30%). Eltanexor demonstrated pharmacokinetics, pharmacodynamics, and molecular markers of response profiles that were like those of selinexor (Table S5, Figures S3 and S4). Treatment-related adverse events (TRAEs) occurring in ≥ 10% of all patients are listed in Table S3. The most common TRAEs of any grade were thrombocytopenia (82%), nausea (54%), and neutropenia (51%). The most common G3 or G4 TRAEs were thrombocytopenia (54%), neutropenia (33%), and anemia (18%). Dose reductions occurred in 38% of patients, and dose interruptions in 72%. In addition to dose reductions and interruptions, thrombocytopenia was managed with platelet transfusions (28%) and the administration of thrombopoietin (TPO) receptor agonists (21%), romiplostim, or eltrombopag. The effectiveness of dose interruptions / TPO administration for alleviating thrombocytopenia is consistent with selinexor studies demonstrating that XPO1 inhibition prevents maturation of the megakaryocyte and not direct cytotoxicity.6 Nausea was managed, on an as needed basis, with prophylactic anti-emetic agent in 74% of patients, typically ondansetron or prochlorperazine, and 33% required an additional anti-nausea medication. There were four serious AEs deemed by the treating physician to be at least possibly related to eltanexor treatment: syncope (60 mg; resolved), acute kidney injury (30 mg + 20 mg dexamethasone, resolved with sequelae), accidental overdose of study drug (5 mg, resolved), and lung infection (20 mg + 20 mg dexamethasone, resolved). Seven deaths occurred while on study (treatment period plus an additional 30 days of safety follow-up): five due to PD, one due to a thromboembolic event occurring in a patient with a medical history of hypertension and deep vein thrombosis, and one due to a subdural hemorrhage (in the context of G4 thrombocytopenia that was not related to eltanexor) during hospitalization. The AEs associated with eltanexor are consistent with those for the first-generation SINE compound, selinexor; however, the incidence and severity of nausea, decreased appetite, hyponatremia, and fatigue were lower than what was reported for selinexor in MM.5 Furthermore, the incidence of neurological AEs (including confusion, syncope, altered mental status, dizziness, depressed level of consciousness, and delirium) in this study was low, with 3 of 39 (8%) patients having a treatment-related neurological AE while on study, and only 1 of the 3 patients having a grade 3 neurological event (syncope). Tolerability of eltanexor was also evident, as patient withdrawal due to TRAEs was relatively low at 8%, while 36% of the patients remained on treatment for over 6 months. The overall response rate (ORR) for the 35 efficacy evaluable patients was 20% (N = 7) and the clinical benefit rate (CBR) was 41%. This included one (2.9%) very good partial response (VGPR), six PRs, and nine minimal responses (MRs). Twelve patients had a best overall response of stable disease (SD) and seven of PD (Table S4). Nine of the 20 (45%) patients treated in the dose escalation phase showed a reduction in M-protein during the first cycle of treatment (Figure S1A). Dexamethasone (20 mg days 1, 3) was added to the treatment regimen of 15 of these patients. Best overall response for the 20 patients in the dose escalation phase included 2 PRs, 5 MRs, 8 SD, and 5 PD. In the dose expansion cohort (n = 15), 20 mg and 30 mg eltanexor (QDx5) plus 20 mg dexamethasone (days 1, 3) starting at C1D1 produced an ORR of 33% (one VGPR and four PRs) and CBR of 60% (four MR). Four patients had SD and two had PD. Deeper and faster responses were observed when dexamethasone was started from C1D1 compared to after C2D1 (Figure S1A,B). While the ORR was higher for patients in the dose expansion cohort treated at 30 mg compared to 20 mg eltanexor (40% vs 20% respectively), the CBR was equivalent (60% for both groups). Fourteen (40%) patients were treated for over 6 months, with four patients receiving treatment for over 1 year, one of whom has been receiving treatment for over 2 years and another for 3.8 years (Figure 1). The median progression free survival (PFS) and overall survival for all patients was 4.47 (95% CI 2.40, 9.26) months and 17.81 (95% CI 11.70, NR) months, respectively (Figure S2), an improved efficacy compared to selinexor QDx2: median PFS 3.7 months, and median OS 8.6 months.5 Such apparent improved efficacy of eltanexor QDx5 compared to selinexor QDx2 was also observed in preclinical models of MM (Karyopharm unpublished results). The median PFS was higher for patients in the dose expansion cohort treated at 20 mg compared to 30 mg eltanexor (8.64 months [95% CI 8.48, 13.83] vs 3.02 months [95% CI 2.99, 9.26], respectively). Based on the totality of safety and efficacy data, a recommended phase 2 dose (RP2D) of 20 mg eltanexor (QDx5) plus 20 mg dexamethasone (days 1, 3) weekly was identified. In conclusion, when given in combination with dexamethasone from C1D1, eltanexor demonstrated significant efficacy with 33% ORR, 60% CBR, and 80% of patients having a reduction in their myeloma markers from baseline. Furthermore, eltanexor was generally well-tolerated. Across all doses and schedules, these heavily pretreated patients (median 7 prior lines) had a median PFS of 4.47 months, suggesting both clinical benefit and tolerability. While an MTD was not reached in this study, based on the totality of the safety and efficacy data, an RP2D of 20 mg eltanexor (QDx5) plus 20 mg dexamethasone (days 1, 3) weekly was identified. These results support the novel approach of inhibiting XPO1 for the treatment of MM. We would like to thank the patients who participated in this trial and their families. In addition, we thank the co-investigators, nurses, and study coordinators at each of the sites, as well as Brittany Eisenbarth-Jenkins, Cielito Sadornas, Tianjun Zhou, and Frances Wong from Karyopharm Therapeutics for their support in this study. Robert Frank Cornell: Employee and stockholder of AbbVie; Research funding from Amgen and Takeda; Consultancy work for Karyopharm, GSK, Takeda; Sanofi. Rachid Baz: Advisory board: Celgene/BMS, Sanofi, Karyopharm, Janssen, AbbVie, GSK, Oncopeptides, Shattuck labs; Research Funding: Celgene/BMS, Sanofi, Karyopharm, Janssen, AbbVie. Joshua R. Richter: Speaker Bureau: Celgene, Janssen. Advisory board/consulting: Celgene, Janssen, Karyopharm, Antengene, oncopeptides, X4 pharmaceuticals, Sanofi, BMS, adaptive biotechnologies, Secura Bio. Adriana Rossi: Research funding BMS, Consultancy work Amgen, Janssen, BMS/Celgene. Dan T. Vogl: Consulting, research funding, and/or advisory role Celgene, Amgen, Karyopharm, Teva, Janssen, Millennium, Acetylon, GlaxoSmithKline, Calithera Biosciences, Constellation. Christine Chen: Research funding from BMS, Sanofi. Honoraria from Janssen, Gilead, Abbvie, Amgen. Chaim Shustik: Honoraria from Janssen, Takeda, Amgen, Sanofi, Abbvie. Mariano Alverez: Employee and stock holder in DarwinHealth, Inc. Yao Shen: Employee in DarwinHealth, Inc. T.J. Unger: Former employee and stock holder in Karyopharm Therapeutics. Erkan Baloglu: Former employee and stock holder in Karyopharm Therapeutics. William Senapedis: Former employee and stock holder in Karyopharm Therapeutics. Xiwen Ma: Employee and stock holder in Karyopharm Therapeutics. Yosef Landesman: Employee and stock holder in Karyopharm Therapeutics. Supraja Narasimhan: Employee and stock holder in Karyopharm Therapeutics. Hongwei Wang: Former employee and stock holder in Karyopharm Therapeutics. Hongmei Xu: Employee and stock holder in Karyopharm Therapeutics. Tracey Marshall: Former employee and stock holder in Karyopharm Therapeutics. Osnat Ben-Shahar: Employee and stock holder in Karyopharm Therapeutics. Xiang Bai: Employee and stock holder in Karyopharm Therapeutics. Hua Chang: Employee and stock holder in Karyopharm Therapeutics. Christopher Walker: Employee and stock holder in Karyopharm Therapeutics. Sharon Shacham: President, CSO, and stock holder in Karyopharm Therapeutics. Michael G. Kauffman: CEO and stock holder in Karyopharm Therapeutics. Craig C. Hofmeister: received NIH funding for the CTO at Ohio State as part of NIH P30CA016058; research grants from Takeda and Oncolytics Biotech; research and personal grants from Janssen, BMS, Sanofi, Nektar, Karyopharm; and personal grants from Imbrium and Oncopeptides, all outside the submitted work. Conception and design: Erkan Baloglu, William Senapedis, Michael Kauffman, Sharon Shacham. Financial support: Michael Kauffman, Sharon Shacham. Administrative/operations support: Tracey Marshall. Provision of study materials or patients: Robert Frank Cornell, Craig C. Hofmeister, Adriana Rossi, Rachid Baz, Chaim Shustik, Joshua R. Richter, Christine Chen, Dan T Vogl. Collection and assembly of data: All authors. Data analysis and interpretation: All Authors. Manuscript writing: T.J. Unger, Robert Frank Cornell, Osnat Ben-Shahar. Final approval of manuscript: All Authors. Accountable for all aspects of the work: All authors. Appendix S1: Supporting Information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

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