SINGLE AGENT ORAL SELINEXOR EXHIBITS DURABLE RESPONSES IN RELAPSED/REFRACTORY DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL) OF BOTH GCB AND NON-GCB SUBTYPES: THE PHASE 2B SADAL STUDY
Author(s): ,
Marie Maerevoet
Affiliations:
Institute Jules Bordet,Brussels,Belgium
,
Jason Westin
Affiliations:
MD Anderson,Houston,United States
,
Catherine Thieblemont
Affiliations:
APHP, Hemato-Oncology,Hopital Saint-Louis,Paris,France
,
Josee Zijlstra
Affiliations:
Lunenburg Lymphoma Phase - I Consortium,VU University Medical Center,Amsterdam,Netherlands
,
Brian T. Hill
Affiliations:
Taussig Cancer Institute,Cleveland Clinic,Cleveland,United States
,
Fatima De La Cruz Vicente
Affiliations:
Hospital University Virgen del Rocio,Sevilla,Spain
,
Sylvain Choquet
Affiliations:
Hospital Pitie Salpetriere,Paris,France
,
Paolo Caimi
Affiliations:
University Hospital Seidman Cancer Center,Cleveland,United States
,
Jason Kaplan
Affiliations:
Feinberg School of Medicine,Northwestern University,Chicago,United States
,
Miguel A. Canales
Affiliations:
Hospital Universitario La Paz,Madrid,Spain
,
John Kuruvilla
Affiliations:
Princess Margaret Hospital,Toronto,Canada
,
George Follows
Affiliations:
NHS Foundation Trust,Cambridge University Teaching Hospitals,Cambridge,United Kingdom
,
Eric Van den Neste
Affiliations:
Cliniques Universitaires UCL Saint-Luc,Brussels,Belgium
,
Julie Meade
Affiliations:
Karyopharm Therapeutics,Newton,United States
,
Brendan Wrigley
Affiliations:
Karyopharm Therapeutics,Newton,United States
,
Marissa Devlin
Affiliations:
Karyopharm Therapeutics,Newton,United States
,
Jean-Richard Saint-Martin
Affiliations:
Karyopharm Therapeutics,Newton,United States
,
Conny Nippgen
Affiliations:
Karyopharm Therapeutics,Newton,United States
,
Humphrey Gardner
Affiliations:
Karyopharm Therapeutics,Newton,United States
,
Sharon Shacham
Affiliations:
Karyopharm Therapeutics,Newton,United States
,
Michael G. Kauffman
Affiliations:
Karyopharm Therapeutics,Newton,United States
Rene-Olivier Casasnovas
Affiliations:
CHU Dijon,Dijon,France
EHA Learning Center. Maerevoet M. Jun 24, 2017; 181756
Marie Maerevoet
Marie Maerevoet

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Abstract
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Abstract: S469

Type: Oral Presentation

Presentation during EHA22: On Saturday, June 24, 2017 from 16:45 - 17:00

Location: Hall C

Background
Patients (pts) with persistent DLBCL after two or more lines of therapy have limited effective treatment options. The nuclear export protein exportin 1 (XPO1) is upregulated in hematologic malignancies, including DLBCL, and has pleiotropic effects on tumorigenesis including functional downregulation of tumor suppressor proteins (TSPs) and increased export and translation of mRNAs for oncoproteins c-Myc and key survival proteins such as Bcl-2. Selinexor (SEL), an oral XPO1 inhibitor, causes sequestration of TSPs including p53, p21, and IkBa, the latter of which serves to suppress NF-kB driven transcription, along with reductions in c-Myc and Bcl-2 family proteins. In a Phase I clinical study, pts with relapsed/refractory (R/R) DLBCL treated with SEL presented an overall response rate (ORR) of 32% including 4 CRs. Interestingly, 2 of these pts remain in CR for >1 yr.

Aims
In this clinical study we assess the efficacy of single agent SEL in pts with R/R DLBCL after ≥2 prior regimens.

Methods
Pts with R/R DLBCL were randomized to 60 or 100 mg of SEL twice weekly (8 doses) per 28-day cycle. Pts were also stratified by DLBCL subtype (GCB or non-GCB). The primary objectives are to determine the ORR and evaluate the safety of 60 vs 100 mg doses. Disease response was assessed by an Independent Central Radiological Review (ICRR), using the Lugano Classification (Cheson, 2014).

Results
72 pts were enrolled: 37 pts on 60 mg (24 M/ 13 F, median age 71 yrs) and 35 pts on 100 mg (23 M/ 12 F, median age 68 yrs). Both groups had a median of 3 prior treatment regimens. The most common related adverse effects (AEs) across both dosing groups (Grade 1/2) were: fatigue (47%), nausea (46%), anorexia (42%), and vomiting (33%). Common Grade 3/4 AEs were: thrombocytopenia (39%), fatigue (18%), neutropenia (18%), and anemia (13%). These were managed with dose interruption/reduction, platelet stimulators, and/or standard supportive care. Grade 3/4 fatigue (26% v 11%) and thrombocytopenia (46% v 32%) were higher in 100 mg arm as compared to the 60 mg arm. Among the 63 evaluable pts (9 pts pending response), the ICRR determined ORR was 28.5% (Table 1). Nine responders, including 6 pts in CR, remain on treatment. Responders on the 60 mg arm have a median time on treatment of 8.9 months as compared with 3.8 months on the 100 mg arm.

 
Table 1. Independent Central Radiological Review – Best Response
Category
N
ORR (%)
CR (%)
PR (%)
SD (%)
DCR (%)
All Doses
63
18 (28.5%)
7 (11.1%)
11 (17.4%)
9 (14.2%)
27 (42.8%)
60 mg
32
9 (28.1%)
4 (12.5%)
5 (15.6%)
3 (9.3%)
12 (37.5%)
100 mg
31
9 (29%)
3 (9.6%)
6 (19.3%)
6 (19.3%)
15 (48.3%)
GCB-Subtype
32
8 (25%)
3 (9.3%)
5 (15.6%)
6 (18.7%)
14 (43.7%)
Non-GCB Subtype
31
10 (32.2%)
4 (12.9%)
6 (19.3%)
3 (9.6%)
13 (41.9%)
 
 

Conclusion
SEL monotherapy shows activity in pts with R/R DLBCL including in pts with GCB subtype. 60 mg SEL twice weekly was more tolerable than 100 mg twice weekly, with fewer interruptions due to toxicity. Objective responses to SEL were durable at 60 mg BIW, suggesting these responses were associated with clinical benefit.

Session topic: 20. Aggressive Non-Hodgkin lymphoma - Clinical

Keyword(s): Phase II, Oral, DLBCL

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