On June 23, 2017 Karyopharm Therapeutics Inc. (Nasdaq:KPTI), a clinical-stage pharmaceutical company, reported updated clinical data from the ongoing Phase 2b Selinexor Against Diffuse Aggressive Lymphoma (SADAL) study evaluating lead product candidate, selinexor (KPT-330), an oral Selective Inhibitor of Nuclear Export / SINE compound, in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) (Press release, Karyopharm, JUN 23, 2017, View Source [SID1234519665]). The data will be featured in an oral presentation at the 22nd Congress of the European Hematology Association (EHA) (Free EHA Whitepaper) taking place June 22-25, 2017 in Madrid, Spain. In the SADAL study, selinexor has achieved a 33.3% overall response rate (ORR) in patients with relapsed or refractory DLBCL after at least two prior multi-agent therapies and who are ineligible for transplantation. The observed responses continue to be durable, with a median duration of response (DOR) of greater than 7 months, including prolonged complete responses (CRs). Schedule your 30 min Free 1stOncology Demo! Updated Phase 2b SADAL Data in Relapsed or Refractory DLBCL
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In the oral presentation, titled "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," Marie Maerevoet, MD, Institute Jules Bordet in Belgium, will present the updated Phase 2b SADAL data. Per the SADAL study protocol, the updated efficacy data were restricted to the interim analysis cohort (n=63), which were previously reported at AACR (Free AACR Whitepaper) 2017, and the updated safety results include updated data on all patients that received at least one dose of selinexor as of the data cutoff date.
Dr. Maerevoet commented, "We are highly encouraged by the impressive response rates that continue to be observed with single-agent oral selinexor in these heavily pretreated patients with DLBCL who have received two or more prior therapies and are not eligible for transplantation, and for whom no standard therapy exists. Along with being clinically active and durable, including prolonged complete responses, the 60mg dose continues to be well tolerated with a low incidence of Grade 3 or greater adverse events, which were manageable with dose modifications and standard supportive care."
A summary of the efficacy data to be presented at EHA (Free EHA Whitepaper) 2017 is outlined in the following table and described below.
Best Responses* in Patients as of 15 May 2017
Category N ORR (%) CR (%) PR (%) SD (%) PD/NE (%)
All patients 63 21 (33.3%) 9 (14.3%) 12 (19.0%) 6 (9.5%) 36 (57.1%)
60 mg 32 11 (34.4%) 4 (12.5%) 7 (21.9%) 1 (3.1%) 20 (62.5%)
100 mg 31 10 (32.2%) 5 (16.1%) 5 (16.1%) 5 (16.1%) 16 (51.6%)
GCB-Subtype 32 9 (28.1%) 4 (12.5%) 5 (15.6%) 3 (9.4%) 20 (62.5%)
Non-GCB-Subtype 31 12 (38.7%) 5 (16.1%) 7 (22.6%) 3 (9.7%) 16 (51.6%)
*Responses were adjudicated according to the Lugano Classification (Cheson, 2014) by an independent central radiological review committee. ORR=Overall Response Rate (CR+PR), DCR=Disease Control Rate (CR+PR+SD), CR=Complete Response, PR=Partial Response, SD=Stable Disease, PD=Progressive Disease, NE=Not Evaluable for Response. Responses are based on interim unaudited data for the first 63 patients (of 90 total patients enrolled as of the data cutoff date).
Based on the modified intention-to-treat analysis of the first 63 patients (median of 3 prior treatment regimens (range 2-5)), as adjudicated by an independent central radiological committee, 21 patients responded (9 patients with a CR and 12 patients with a PR) for an ORR 33.3%. An additional 6 patients experienced SD, for a disease control rate of 42.9%. The median DOR across all patients was greater than 7 months and responses tended to occur rapidly with a median of 2 months to onset. Among patients who responded, the median time on treatment was 9 months with a follow up of 12.8 months. As of the data cutoff date, 9 patients who responded remained on treatment, including 6 patients with a CR.
The median overall survival was 8 months for all patients on the study, consistent with the 6-7 month published survival data in this population, indicating that their prognosis is extremely poor. As of the data cutoff date, median survival for the patients with PR or CR had not been reached and is over 9 months; the median survival for patients with SD or PD, NE disease was 4.8 months.
Selinexor also showed robust, single-agent activity against GCB and non-GCB subtypes of DLBCL: Of the 32 patients with DLBCL of the GCB-subtype, 9 responded (4 patients with a CR, 5 patients with a PR) for an ORR of 28.1%. Of the 31 patients with DLBCL of the non-GCB (or ABC)-subtype, 12 responded (5 patients with a CR, 7 patients with a PR) for an ORR of 38.7%. Finally, amongst the 14 patients with "double-" or "triple-hit" DLBCLs, the ORR was 35%, indicating that selinexor has clear activity in this population, which usually has a particularly poor prognosis.
Among the 90 patients evaluated for safety as of the data cutoff date, the most common adverse events (AEs) across both dosing groups were fatigue (61%), nausea (51%), thrombocytopenia (50%), anorexia (49%), vomiting (31%) and anemia (30%), and were primarily grades 1 and 2 and were managed with dose modifications and/or standard supportive care. As expected, the most common grade 3 and 4 AEs in the 60mg arm were thrombocytopenia (28%), neutropenia (17%), anemia (15%), and fatigue (11%) and were manageable with dose modifications and/or standard supportive care.
As previously announced, in consultation with the U.S. Food and Drug Administration (FDA), Karyopharm has amended the SADAL study protocol to become a single-arm study focusing solely on single-agent selinexor dosed at 60mg twice weekly and has eliminated the 100mg arm. The FDA has agreed that the single-arm trial design appears appropriate for accelerated approval in DLBCL, though eligibility for accelerated approval will depend on the complete trial results and available therapies at the time of regulatory action. In total, the SADAL study is expected to enroll up to a total of 130 patients in the 60mg single-arm cohort and Karyopharm plans to report top-line results in the second half of 2018.
"The IRC-confirmed durable responses achieved with single-agent oral selinexor have improved over time and continue to demonstrate robust single-agent activity and prolonged responses in patients with heavily pretreated DLBCL, and these responses correlate with improved overall survival," said Sharon Shacham, PhD, MBA, President and Chief Scientific Officer of Karyopharm. "We were particularly pleased to see a 35% response rate in the double- or triple-hit subgroup, a particularly difficult to treat patient population. The 60mg treatment arm is enrolling on track, and we look forward to reporting top-line data from the SADAL study in the second half of 2018. Assuming a positive outcome, we expect to seek accelerated approval for selinexor in DLBCL."
Details for the Oral Presentation at EHA (Free EHA Whitepaper) 2017:
Title: 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
Presenter: Marie Maerevoet, Institute Jules Bordet, Brussels, Belgium
Abstract code: S469
Topic: Aggressive Non-Hodgkin lymphoma — Clinical
Session: Aggressive Non-Hodgkin lymphoma — Relapsed/refractory
Location: Hall C
Date and Time: Saturday, June 24, 2017 from 14:45 – 17:00 CET
About Selinexor
Selinexor (KPT-330) is a first-in-class, oral Selective Inhibitor of Nuclear Export / SINE compound. Selinexor functions by binding with and inhibiting the nuclear export protein XPO1 (also called CRM1), leading to the accumulation of tumor suppressor proteins in the cell nucleus. This reinitiates and amplifies their tumor suppressor function and is believed to lead to the selective induction of apoptosis in cancer cells, while largely sparing normal cells. To date, over 2,000 patients have been treated with selinexor and it is currently being evaluated in several mid- and later-phase clinical trials across multiple cancer indications, including in multiple myeloma in a pivotal, randomized Phase 3 study in combination with Velcade (bortezomib) and low-dose dexamethasone (BOSTON), in combination with low-dose dexamethasone (STORM) and backbone therapies (STOMP), and in diffuse large B-cell lymphoma (SADAL), and liposarcoma (SEAL), among others. Additional Phase 1, Phase 2 and Phase 3 studies are ongoing or currently planned, including multiple studies in combination with one or more approved therapies in a variety of tumor types to further inform the Company’s clinical development priorities for selinexor. Additional clinical trial information for selinexor is available at www.clinicaltrials.gov.