A PHASE 1B/2 STUDY OF SELINEXOR IN COMBINATION WITH BACKCONE THERAPIES FOR TREATMENT OF RELAPSED/REFACTORY MULTIPLE MYELOMA
Author(s): ,
Nizar Bahlis
Affiliations:
Southern Alberta Cancer Research Institute,Calgary,Canada
,
Christine Chen
Affiliations:
Princess Margaret Cancer Center,Toronto,Canada
,
Michael Sebag
Affiliations:
Royal Victoria Hospital,Montreal,Canada
,
Chris Venner
Affiliations:
Cross Cancer Institute,Edmonton,Canada
,
Tom Kouroukis
Affiliations:
Juravinski Cancer Centre,Hamilton,Canada
,
Heather Sutherland
Affiliations:
Vancouver General Hospital,Vancouver,Canada
,
Richard LeBlanc
Affiliations:
Hôpital Maisonneuve-Rosemont,Montreal,Canada
,
Debra Bergstrom
Affiliations:
Memorial Hospital of Newfoundland,St. John's,Canada
,
Arleigh McCurdy
Affiliations:
The Ottawa Hospital,Ottawa,Canada
,
Marc Lalancette
Affiliations:
Hotel-Dieu de Québec,Québec,Canada
,
Cassandra Choe-Juliak
Affiliations:
Karyopharm Therapeutics,Newton,United States
,
Carla Picklesimer
Affiliations:
Karyopharm Therapeutics,Newton,United States
,
Jean-Richard Saint-Martin
Affiliations:
Karyopharm Therapeutics,Newton,United States
,
Jacqueline Jeha
Affiliations:
Karyopharm Therapeutics,Newton,United States
,
Michael Kauffman
Affiliations:
Karyopharm Therapeutics,Newton,United States
,
Sharon Shacham
Affiliations:
Karyopharm Therapeutics,Newton,United States
Rami Kotb
Affiliations:
Cancer Care Manitoba,Winnipeg,Canada
EHA Learning Center. Bahlis N. Jun 10, 2016; 133264
Mr. Nizar Bahlis
Mr. Nizar Bahlis
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Abstract
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Abstract: P277

Type: Poster Presentation

Presentation during EHA21: On Friday, June 10, 2016 from 17:15 - 18:45

Location: Poster area (Hall H)

Background
The nuclear export protein exportin 1, (XPO1) is overexpressed in a wide variety of cancers including multiple myeloma (MM). Selinexor is an oral Selective Inhibitor of Nuclear Export (SINE), specifically a XPO1 antagonist. Selinexor forces nuclear retention and reactivation of tumor suppressor proteins (TSPs; NF-κB, p53 and FOXO) and reduction of many proto-oncogenes, including MDM2, MYC and Cyclin D. Preclinical activity for selinexor has been demonstrated in combination with pomalidomide (pom), bortezomib (bort) or lenalidomide (len). There is in vitro and in vivo evidence of selinexor synergy with bort (e.g. proteasome inhibitors) through repression of NF-κB pathway and induction of autophagy in MM. In MM xenografts model, selinexor in combination with IMiDs have shown synergy in tumor growth inhibition and increased overall survival when compared to single agents alone. In addition, phase 1 and 2 clinical studies demonstrated selinexor single agent anti-myeloma efficacy.

Aims
To independently assess the efficacy and safety of three combination therapies for the treatment of patients (pts) with relapsed/refractory MM. The combinations are selinexor + dexamethasone (dex) + either Pom (SdP), Bort (SdB), or Len (SdL).

Methods
The dose escalation phase, conducted via the standard 3+3 design, consists of 3 treatment arms (SdP, SdB, and SdL), each arm including two treatment cohorts  (once-weekly (80 mg, 100 mg) vs. twice-weekly (60 mg, 80 mg) selinexor dosing).  These 3 treatment arms are evaluated in parallel. Pom (4 mg), len (25 mg) and dex (20 mg with each selinexor dose) will not be dose escalated. For the SdB arm, bort (1.3 mg/m2 given SC) will be dose escalated from once-weekly to twice-weekly dosing (consistent with its approved, labeled dose).

Results
As of 10-Feb-2016, 4 pts (2M/2F, median of 8 prior regimens, median age 61 yrs) have been enrolled in the SdP arm. Ten pts (5M/5F, median of 8 prior regimens, median age 65 yrs) have been enrolled in the SdB arm. Common grade 1/2 adverse events (AEs) in the SdP arm are nausea (2 pts, 50%) and dysgeusia (2 pts, 50%). One grade 4 AE, neutropenia, was reported in the SdP arm. The most common related grade 1/2 AEs in the SdB are fatigue (2 pts, 20%), nausea (1 pt, 10%), and diarrhea (1 pt, 10%). Thrombocytopenia (5 pts, 50%) is the only Grade 3 AE reported in the SdB arm. Two pts were evaluable for response in SdP arm and achieved a very good partial response (VGPR, n=1) and a minor response (MR, n=1). Seven pts were evaluable for responses in the SdB arm including 3 partial responses (PR, 2 pts were bort refractory and 2 with del17p in > 60%), 2 MR, 1 stable disease and 1 progressive disease.

Conclusion
Significant responses are observed in both treatment combinations of selinexor + dex + pom and selinexor + dex + bort, even in heavily pretreated patients with del17p and/or prior refractoriness to bortezomib. In patients with relapsed/refractory MM whose disease has progressed after PI and/or IMIDs based regimen, the addition of selinexor to bortezomib or pomalidomide is well tolerated.  The early response rate observed is promising given the history of extensive pretreatment in this patient group.  Updated results from this ongoing phase I/II trial will be presented at the meeting. (clinicalTrials.gov      #NCT02343042)

Session topic: Innovative therapies for MM 1

Keyword(s): Clinical trial, Multiple myeloma, Phase I/II
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