Nagesh Kalakonda1, Marie Maerevoet2, Federica Cavallo3, George Follows4, Andre Goy5, Joost S P Vermaat6, Olivier Casasnovas7, Nada Hamad8, Josée M Zijlstra9, Sameer Bakhshi10, Reda Bouabdallah11, Sylvain Choquet12, Ronit Gurion13, Brian Hill14, Ulrich Jaeger15, Juan Manuel Sancho16, Michael Schuster17, Catherine Thieblemont18, Fátima De la Cruz19, Miklos Egyed20, Sourav Mishra21, Fritz Offner22, Theodoros P Vassilakopoulos23, Krzysztof Warzocha24, Daniel McCarthy25, Xiwen Ma25, Kelly Corona25, Jean-Richard Saint-Martin25, Hua Chang25, Yosef Landesman25, Anita Joshi25, Hongwei Wang25, Jatin Shah25, Sharon Shacham25, Michael Kauffman25, Eric Van Den Neste26, Miguel A Canales27. 1. University of Liverpool, Liverpool, UK. Electronic address: nagesh.kalakonda@liverpool.ac.uk. 2. Institut Jules Bordet, Brussels, Belgium. 3. Department of Molecular Biotechnologies and Health Sciences, Division of Hematology, University of Torino, Turin, Italy. 4. Addenbrooke's Hospital, Cambridge, UK. 5. John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ, USA. 6. Leiden University Medical Center, Leiden, Netherlands. 7. Hématologie Clinique, Dijon, France. 8. St Vincent's Hospital Sydney, Darlinghurst, NSW, Australia. 9. Amsterdam UMC, Vrije Universiteit, Cancer Center, Amsterdam, Netherlands. 10. Dr B R Ambedkar Institute Rotary Cancer Hospital AIIMS, New Delhi, India. 11. Institut Paoli-Calmettes, Marseille, France. 12. Hôpital Pitié Salpêtrière, Paris, France. 13. Rabin Medical Centre, Petah Tiqwa, Israel; Tel Aviv University, Petah Tiqwa, Israel. 14. Cleveland Clinic, Cleveland, OH, USA. 15. Medical University of Vienna, Vienna, Austria. 16. ICO-IJC Hospital Universitari Germans Trias I Pujol, Barcelona, Spain. 17. Stony Brook University, Stony Brook NY, USA. 18. Saint-Louis Hospital, Paris, France; Paris Diderot University, Paris, France. 19. Hospital Universitario Virgen del Rocio, Sevilla, Spain. 20. Teaching Hospital Mór Kaposi, Kaposvár, Hungary. 21. Institute of Medical Sciences & SUM Hospital, Odisha, India. 22. Gent University Hospital, Gent Belgium. 23. Laikon General Hospital National, Athens, Greece; Kapodistrian University of Athens, Athens, Greece. 24. Instytut Hematologii i Transfuzjologii, Warszawa, Poland. 25. Karyopharm Therapeutics Inc, Newton, MA, USA. 26. Cliniques Universitaires Saint-Luc, Brussels, Belgium. 27. Hospital Universitario La Paz, Madrid, Spain.
Abstract
BACKGROUND:Relapsed or refractory diffuse large B-cell lymphoma (DLBCL) is an aggressive cancer with a median overall survival of less than 6 months. We aimed to assess the response to single-agent selinexor, an oral selective inhibitor of nuclear export, in patients with relapsed or refractory DLBCL who had no therapeutic options of potential clinical benefit. METHODS: SADAL was a multicentre, multinational, open-label, phase 2b study done in 59 sites in 19 countries. Patients aged 18 years or older with pathologically confirmed diffuse large B-cell lymphoma, an Eastern Cooperative Oncology Group performance status of 2 or less, who had received two to five lines of previous therapies, and progressed after or were not candidates for autologous stem-cell transplantation were enrolled. Germinal centre B-cell or non-germinal centre B-cell tumour subtype and double or triple expressor status were determined by immunohistochemistry and double or triple hit status was determined by cytogenetics. Patients received 60 mg selinexor orally on days 1 and 3 weekly until disease progression or unacceptable toxicity. The study was initially designed to evaluate both 60 mg and 100 mg twice-weekly doses of selinexor; however, the 100 mg dose was discontinued in the protocol (version 7.0) on March 29, 2017, when an improved therapeutic window was observed at 60 mg. Primary outcome was overall response rate. The primary outcome and safety were assessed in all patients who received 60 mg selinexor under protocol version 6.0, or enrolled under protocol versions 7.0 or higher and received at least one dose of selinexor. This trial is registered at ClinicalTrials.gov, NCT02227251 (active but not enrolling). FINDINGS: Between Oct 21, 2015, and Nov 2, 2019, 267 patients were randomly assigned, with 175 allocated to the 60 mg group and 92 to the discontinued 100 mg group. 48 patients assigned to the 60 mg group were excluded due to enrolment before version 6.0 of the protocol; the remaining 127 patients receivedselinexor 60 mg and were included in analyses of primary outcome and safety. The overall response rate was 28% (36/127; 95% CI 20·7-37·0); 15 (12%) achieved a complete response and 21 (17%) a partial response. The most common grade 3-4 adverse events were thrombocytopenia (n=58), neutropenia (n=31), anaemia (n=28), fatigue (n=14), hyponatraemia (n=10), and nausea (n=8). The most common serious adverse events were pyrexia (n=9), pneumonia (n=6), and sepsis (n=6). There were no deaths judged as related to treatment with selinexor. INTERPRETATION: Single-drug oral selinexor induced durable responses and had a manageable adverse events profile in patients with relapsed or refractory DLBCL who received at least two lines of previouschemoimmunotherapy. Selinexor could be considered a new oral, non-cytotoxic treatment option in this setting. FUNDING: Karyopharm Therapeutics Inc.
RCT Entities:
BACKGROUND: Relapsed or refractory diffuse large B-cell lymphoma (DLBCL) is an aggressive cancer with a median overall survival of less than 6 months. We aimed to assess the response to single-agent selinexor, an oral selective inhibitor of nuclear export, in patients with relapsed or refractory DLBCL who had no therapeutic options of potential clinical benefit. METHODS: SADAL was a multicentre, multinational, open-label, phase 2b study done in 59 sites in 19 countries. Patients aged 18 years or older with pathologically confirmed diffuse large B-cell lymphoma, an Eastern Cooperative Oncology Group performance status of 2 or less, who had received two to five lines of previous therapies, and progressed after or were not candidates for autologous stem-cell transplantation were enrolled. Germinal centre B-cell or non-germinal centre B-cell tumour subtype and double or triple expressor status were determined by immunohistochemistry and double or triple hit status was determined by cytogenetics. Patients received 60 mg selinexor orally on days 1 and 3 weekly until disease progression or unacceptable toxicity. The study was initially designed to evaluate both 60 mg and 100 mg twice-weekly doses of selinexor; however, the 100 mg dose was discontinued in the protocol (version 7.0) on March 29, 2017, when an improved therapeutic window was observed at 60 mg. Primary outcome was overall response rate. The primary outcome and safety were assessed in all patients who received 60 mg selinexor under protocol version 6.0, or enrolled under protocol versions 7.0 or higher and received at least one dose of selinexor. This trial is registered at ClinicalTrials.gov, NCT02227251 (active but not enrolling). FINDINGS: Between Oct 21, 2015, and Nov 2, 2019, 267 patients were randomly assigned, with 175 allocated to the 60 mg group and 92 to the discontinued 100 mg group. 48 patients assigned to the 60 mg group were excluded due to enrolment before version 6.0 of the protocol; the remaining 127 patients received selinexor 60 mg and were included in analyses of primary outcome and safety. The overall response rate was 28% (36/127; 95% CI 20·7-37·0); 15 (12%) achieved a complete response and 21 (17%) a partial response. The most common grade 3-4 adverse events were thrombocytopenia (n=58), neutropenia (n=31), anaemia (n=28), fatigue (n=14), hyponatraemia (n=10), and nausea (n=8). The most common serious adverse events were pyrexia (n=9), pneumonia (n=6), and sepsis (n=6). There were no deaths judged as related to treatment with selinexor. INTERPRETATION: Single-drug oral selinexor induced durable responses and had a manageable adverse events profile in patients with relapsed or refractory DLBCL who received at least two lines of previous chemoimmunotherapy. Selinexor could be considered a new oral, non-cytotoxic treatment option in this setting. FUNDING: Karyopharm Therapeutics Inc.
Authors: Brian Hess; William Townsend; Weiyun Ai; Anastasios Stathis; Melhem Solh; Juan Pablo Alderuccio; David Ungar; Sam Liao; Lori Liao; Lisa Khouri; Xiaoyan Zhang; Joseph Boni Journal: AAPS J Date: 2021-12-10 Impact factor: 4.009
Authors: Jithma P Abeykoon; Xiaosheng Wu; Kevin E Nowakowski; Surendra Dasari; Jonas Paludo; S John Weroha; Chunling Hu; Xiaonan Hou; Jann N Sarkaria; Ann C Mladek; Jessica L Phillips; Andrew L Feldman; Aishwarya Ravindran; Rebecca L King; Justin Boysen; Mary J Stenson; Ryan M Carr; Michelle K Manske; Julian R Molina; Prashant Kapoor; Sameer A Parikh; Shaji Kumar; Steven I Robinson; Jia Yu; Judy C Boughey; Liewei Wang; Matthew P Goetz; Fergus J Couch; Mrinal M Patnaik; Thomas E Witzig Journal: Blood Date: 2021-01-28 Impact factor: 22.113
Authors: Mehdi Hamadani; John Radford; Carmelo Carlo-Stella; Paolo F Caimi; Erin Reid; Owen A O'Connor; Jay M Feingold; Kirit M Ardeshna; William Townsend; Melhem Solh; Leonard T Heffner; David Ungar; Luqiang Wang; Joseph Boni; Karin Havenith; Yajuan Qin; Brad S Kahl Journal: Blood Date: 2021-05-13 Impact factor: 22.113
Authors: Yvette L Kasamon; Lauren S L Price; Olanrewaju O Okusanya; Nicholas C Richardson; Ruo-Jing Li; Lian Ma; Yu-Te Wu; Marc Theoret; Richard Pazdur; Nicole J Gormley Journal: Oncologist Date: 2021-07-01