Background: Relapsed or refractory diffuse large B‑cell lymphoma (RR DLBCL) is an aggressive cancer with a median survival of less than 6 months. The SADAL trial aims to assess the response to the oral selective inhibitor of nuclear export (SINE) selinexor in patients with RR DLBCL who have no therapeutic options of demonstrated clinical benefit. Methods: SADAL was a multicenter, open-label Phase 2b study conducted at 59 sites globally. Patients 18 years with previously treated, pathologically confirmed de novo DLBCL, or DLBCL transformed from previously diagnosed indolent lymphoma, and having received at least two prior therapies were enrolled. Germinal center B-cell (GCB) or non-GCB tumor subtype and double/triple expressor status were determined by immunohistochemistry and double/triple hit status was determined by cytogenetic assays. Patients received 60 mg selinexor orally on days 1 and 3 weekly until disease progression or unacceptable toxicity. The primary outcome was overall response rate (ORR) by central radiologic review. A modified intent-to-treat population was used for all efficacy endpoints. Findings: 127 patients were enrolled from October 21, 2015 through November 2, 2019. The ORR was 28.3% (95% CI: 20.7%, 37.0%), including complete response in 15 (11.8%) and partial response in 21 (16.5%) patients. Median overall survival (OS) was 9.1 months (95% CI: 6.6, 15.1) with longer OS observed in responding patients. Responses were observed across different subgroups regardless of age, gender, prior therapy, DLBCL subtype, refractory status or prior ASCT therapy. Adverse events were generally reversible and managed with dose modifications and/or standard supportive care. Interpretation: In both GCB- and non-GCB DLBCL subtypes, single agent oral selinexor induced durable responses which were associated with longer survival. Selinexor may be a new oral, non-cytotoxic treatment option for patients with RR DLBCL after two lines of chemo-immunotherapy. Trial Registration: This trial is registered at ClinicalTrials.gov, NCT02227251. Funding Statement: This study (NCT02227251) was funded by Karyopharm Therapeutics Inc, Newton, Massachusetts, USA, which provided all study materials. Declaration of Interests: NK reports research support from Verastem, Gilead, Celgene, and Roche, as well as honoraria from Gilead, Janssen, and Karyopharm. FC reports personal fees from Takeda, Gilead, and Janssen, outside the submitted work. MC reports personal fees from Celgene, Gilead, Janssen, Karyopharm, Novartis, Roche, Sandoz, and Servier outside the submitted work. GF reports personal fees from Karyopharm and Roche, outside the submitted work. AG reports personal fees and honoraria from AstraZeneca, personal fees and board membership from Cota and Kite/Gilead, personal fees from Janssen, Celgene, Acerta, and research funding from Constellation, Bayer, CALBG, Genentech, Hoffman-La Roche, MD Anderson, Morphosys, Pharmacyclics, and the University of Nebraska, outside the submitted work. OC reports grants, personal fees, and non-financial support from Roche, personal fees and non-financial support from Takeda, BMS, Amgen, Janssen, Abbvie, grants and personal fees from Gilead, and personal fees from Merck, outside the submitted work. BH reports grants and personal fees from Karyopharm, outside the submitted work. UJ reports personal fees from Karyopharm, during the conduct of the study; grants and personal fees from AbbVie, Celgene, Gilead, Janssen, Novartis, Roche, Takeda, Amgen, Miltenyi, and BMS, outside the submitted work. JMS reports honoraria from Roche, Janssen, Gilead, Celgene, Novartis outside the submitted work. MS reports personal fees from Karyopharm during the conduct of the study, and personal fees from Amgen, Abbvie, Gilead, Takeda, Celgene, Pharmacyclics, Astellas, Verastem, Merck, Novartis, Genentech, and Seattle Genetics, outside the submitted work. TPV reports honoraria from WinMedica, Astellas, and Gilead, honoraria, advisory board membership and research support from Takeda, honoraria and advisory board membership from Roche, Bristol, Genesis, and Novartis, advisory board membership at Janssen, honoraria and research support from Merck and Amgen, and research support from Pfizer and Karyopharm. AJ reports personal fees from Karyopharm Therapeutics during the conduct of the study. YL reports personal fees from Karyopharm Therapeutics, outside the submitted work. HC, YL, XM, KC, DM, HW, JS, JRS, SS, and MK are employees of Karyopharm. AJ is a consultant for Karyopharm. MK and SS are stockholders of Karyopharm. SS holds patents (8999996, 9079865, 9714226, PCT/US12/048319, and I574957) on hydrazide containing nuclear transport modulators and uses, and pending patents (PCT/US12/048319, 499/2012, PI20102724, and 2012000928) on hydrazide-containing nuclear transport modulators and uses. All other authors declare no competing interests. Ethics Approval Statement: The institutional review board or independent ethics committee at each study center approved the protocol, and the study was performed in accordance with the International Conference on Harmonisation Good Clinical Practice guidelines and the principles of the Declaration of Helsinki.