Abstract
Background: The nuclear export protein, XPO1 is overexpressed in all types of malignant lymphoma. The SINE selinexor (KPT-330) is a slowly reversible XPO1 antagonist that forces the nuclear retention and activation of over 10 tumor suppressor proteins (TSP) such as p53, IkB, FOXO and p21. In addition, selinexor inhibits the nuclear export and the translation of oncogenic mRNAs such as c-myc and Bcl-XL levels. Together these effects result in apoptosis of cancer cells in preclinical models of both T- and B- cell NHL. In DLBCL cell lines (n=10), selinexor induced potent cytotoxicity against both germinal center (GCB) and nonGCB including those with high MYC and/or BCL2/6 protein levels. Methods: Selinexor was administered orally for 4-10 doses in a 28-day cycle in this phase 1 study. Serial tumor biopsies were performed. Response evaluation was performed in cycle 1 and 2 and then every 2 cycles. All pts had heavily pretreated NHL with documented progressive disease (PD) on study entry. Results: 58 pts (34 males 24 females; median age 62 yrs; ECOG PS 0/1/2: 19/35/4; median prior regimens: 3) received selinexor across 13 dose levels (3 to 80 mg/m2). The recommended Phase 2 dose is 60 mg/m2 based on results across all Phase 1 studies. Grade 3/4 events (>5%) include thrombocytopenia (31%), neutropenia (22%), fatigue (10%), and anemia (7%). The most common Grade 1/2 AEs were: nausea (66%), anorexia (47%), fatigue (40%), and vomiting (40%) that were manageable with supportive care and were seen less frequently following cycle 1. Increases in XPO1 mRNA levels were observed at all doses and sustained for 4-48 hours, supporting twice weekly dosing. Tumor biopsies confirmed TSP nuclear localization, c-myc reductions, and apoptosis induction of cancer cells. Objective responses were observed in all classes of NHL studied (Table 1). An objective response rate (ORR) of 31% was observed across all NHL types. An ORR of 40% was observed in pts with rel/ref aggressive B-NHL (DLBCL, Follicular NHL grade 3b (FLgrd3b) and transformed NHL) at doses ³60 mg/m2 vs an ORR of 33% at 23-50 mg/m2 and 25% at ²20 mg/m2. Across all NHL types, time to best response was delayed, including 5 complete responses (CR) (4 in DLBCL and 1 T-NHL). Nine pts out of 34 have remained on therapy for >6-23 months without clinically significant cumulative toxicities or major organ dysfunction. Conclusions: Selinexor treatment is generally well tolerated with supportive care and can be given over a prolonged period. Durable single agent activity in pts with heavily pretreated NHL has been observed. Phase 2 studies in DLBCL, Richter's transformation and T-NHL of single agent selinexor as well as in combination with other agents including CD20 antibodies are expected to begin in the near future.
| Cancer Type . | Selinexor Dose (mg/m2) . | N* . | ORR (%) . | CR (%) . | PR (%) . | SD (%) . | PD (%) . | WC/NE (%) . |
|---|---|---|---|---|---|---|---|---|
| Aggressive B-NHL (DLBCL, FLgrd3b, Transformed) | ≤20 | 4 | 1 (25%) | -- | 1 (25%) | 1 (25%) | 2 (50%) | -- |
| 20 – 50 | 21 | 7 (33%) | 4 (19%) | 3 (14%) | 5 (24%) | 6 (29%) | 3 (14%) | |
| ≥60* | 10 | 4 (40%) | -- | 4 (40%) | 4 (40%) | -- | 2 (20%) | |
| Follicular & Other Indolent NHL | ≤30 | 4 | -- | -- | -- | 4 (100%) | -- | -- |
| ≥35 | 4 | 2 (50%) | -- | 2 (50%) | 1 (25%) | -- | 1 (25%) | |
| Mantle Cell Lymphoma | ≤30 | 2 | 1 (50%) | -- | 1 (50%) | 1 (50%) | -- | -- |
| ≥35 | 2 | -- | -- | -- | -- | 1 (50%) | 1 (50%) | |
| T-Cell Lymphoma | ≤30 | 4 | -- | -- | -- | 2 (50%) | -- | 2 (50%) |
| ≥35 | 1 | 1 (100%) | 1 (100%) | -- | -- | -- | -- | |
| Richter's Transformation | ≤30 | 3 | 1 (33%) | -- | 1 (33%) | 2 (67%) | -- | -- |
| ≥35 | 3 | 1 (33%) | -- | 1 (33%) | -- | -- | 2 (67%) | |
| TOTAL | 58 | 18 (31%) | 5 (9%) | 13 (22%) | 20 (34%) | 9 (16%) | 11 (19%) | |
| Cancer Type . | Selinexor Dose (mg/m2) . | N* . | ORR (%) . | CR (%) . | PR (%) . | SD (%) . | PD (%) . | WC/NE (%) . |
|---|---|---|---|---|---|---|---|---|
| Aggressive B-NHL (DLBCL, FLgrd3b, Transformed) | ≤20 | 4 | 1 (25%) | -- | 1 (25%) | 1 (25%) | 2 (50%) | -- |
| 20 – 50 | 21 | 7 (33%) | 4 (19%) | 3 (14%) | 5 (24%) | 6 (29%) | 3 (14%) | |
| ≥60* | 10 | 4 (40%) | -- | 4 (40%) | 4 (40%) | -- | 2 (20%) | |
| Follicular & Other Indolent NHL | ≤30 | 4 | -- | -- | -- | 4 (100%) | -- | -- |
| ≥35 | 4 | 2 (50%) | -- | 2 (50%) | 1 (25%) | -- | 1 (25%) | |
| Mantle Cell Lymphoma | ≤30 | 2 | 1 (50%) | -- | 1 (50%) | 1 (50%) | -- | -- |
| ≥35 | 2 | -- | -- | -- | -- | 1 (50%) | 1 (50%) | |
| T-Cell Lymphoma | ≤30 | 4 | -- | -- | -- | 2 (50%) | -- | 2 (50%) |
| ≥35 | 1 | 1 (100%) | 1 (100%) | -- | -- | -- | -- | |
| Richter's Transformation | ≤30 | 3 | 1 (33%) | -- | 1 (33%) | 2 (67%) | -- | -- |
| ≥35 | 3 | 1 (33%) | -- | 1 (33%) | -- | -- | 2 (67%) | |
| TOTAL | 58 | 18 (31%) | 5 (9%) | 13 (22%) | 20 (34%) | 9 (16%) | 11 (19%) | |
* First pt in this population was dosed on 23-July-2012
ORR=Objective Response Rate; CR=Complete Response; PR=Partial Response; SD=Stable Disease; PD=Progressive Disease; WC=Withdrew Consent; NE=Non-Evaluable
Byrd:Pharmacyclics, Genentech: Research Funding. Porcu:Infinity: Research Funding; Seattle genetics: Research Funding; Actelion: Honoraria; Celgene: Honoraria; United States Cutaneous Lymphoma Consortium: Membership on an entity's Board of Directors or advisory committees; Cutaneous Lymphoma Foundation: Membership on an entity's Board of Directors or advisory committees. Stone:AbbVie, Inc: Consultancy; Agios: Consultancy; Amgen: Consultancy; Celator: Consultancy; Celgene: Consultancy; Roche: Consultancy. Baz:Celgene: Research Funding; Millennium: Research Funding; Bristol Myers Squibb: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding. Flinn:AstraZeneca: Research Funding. Kukreti:Celgene: Honoraria. Landesman:Karyopharm Therapeutics: Employment. Klebanov:Karyopharm Therpeutics: Employment. Shacham:Karyopharm Therapeutics: Employment. Saint-Martin:Karyopharm Therpeutics: Employment. Marshall:Karyopharm Therpeutics: Employment. McCartney:Karyopharm Therpeutics: Employment. McCauley:Karyopharm Therapeutics: Employment, Equity Ownership. Carlson:Karyopharm Therapeutics: Employment. Norori:Karyopharm Therpeutics: Consultancy. Savona:Karyopharm Therpeutics: Membership on an entity's Board of Directors or advisory committees. Rashal:Karyopharm Therapeutics: Employment. Mirza:Karyopharm Therpeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kauffman:Karyopharm Therapeutics: Employment, Equity Ownership. Shacham:Karyopharm Therpeutics: Employment, Equity Ownership.
Author notes
Asterisk with author names denotes non-ASH members.
