selinexor in combinaon with bortezomib and dexamethasone … · 2019. 5. 8. · ash 58th annual...

ASH 58thAnnualMee/ng&Exposi/onSanDiego,CADecember3–6,2016

SelinexorinCombina.onwithBortezomibandDexamethasone(SVd)DemonstratesSignificant

Ac.vityinPa.entswithRefractoryMM:ResultsofPhaseISTOMPTrial(MCRN02)

Nizar J. Bahlis1, Rami Kotb2, Michael Sebag3, Heather Sutherland4, Richard LeBlanc5, Darrell White6, Chris Venner7, Tom Kouroukis8, Debra Bergstrom9, Arleigh McCurdy10, Marc

Lalancette11, William Bensinger12, Suzanne Lentzsch13, Aldo Del Col16, Michael Kauffman14, Sharon Shacham14, Jacqueline Jeha14, Carla Picklesimer14, Jean-Richard Saint-Martin14,

Cassandra Choe-Juliak14, Christine Chen15 (1) Southern Alberta Cancer Research Institute, Calgary, Alberta (2) Cancer Care Manitoba, Winnipeg, Manitoba (3) Royal Victoria Hospital, Montreal, Québec (4) Vancouver General Hospital, Vancouver, British Columbia (5) Hôpital Maisonneuve-Rosemont, Montreal, Quebec (6) Queen Elizabeth II Health Sciences Center, Halifax; Nova Scotia (7) Cross Cancer Institute, Edmonton, Alberta (8) Juravinski Cancer Centre, Hamilton, Ontario (9) Memorial Hospital of Newfoundland, St. John’s Newfoundland (10) The Ottawa Hospital, Ottawa, Ontario (11) Hotel-Dieu de Québec, Quebec, Quebec (12) Swedish Cancer Center, Seattle; WA (13) Columbia University, New York; NY (14) Karyopharm Therapeutics, Newton, MA (15) Princess Margaret Cancer Center, Toronto, Ontario (16) Myeloma Canada, Laval, Quebec


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§  Our patients and their families

§  Myeloma Canada Research Network Consortium (MCRN) Investigators:

ThisstudywassponsoredbyKaryopharmTherapeu/cs

Acknowledgements

§  Southern Alberta Cancer Research Institute

§  Cancer Care Manitoba

§  Royal Victoria Hospital

§  Vancouver General Hospital

§  Hôpital Maisonneuve-Rosemont

§  Queen Elizabeth II Health Sciences Center

§  Cross Cancer Institute

§  Juravinski Cancer Centre

§  Memorial Hospital of Newfoundland

§  The Ottawa Hospital

§  Hotel-Dieu de Québec

§  Swedish Cancer Center

§  Columbia University

§  Princess Margaret Cancer Center


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§  Selinexor is a first-in-class exportin 1 (XPO1) inhibitor: Nuclear retention and activation of TSPs

Nuclear retention of GR in the presence of steroids Suppresses oncoproteins expression

§  Bortezomib is a first-in-class proteasome inhibitor (PI)

that inhibits the 26S proteasome disrupting proteins homeostasis and inducing ER stress response.

§  Selinexor synergizes with PI (bortezomib) through •  increased nuclear IκB retention and inhibition of

NFκB transcriptional activity. •  Induction of ribosomal stress response.

MechanismofAc.on–Selinexor+Bortezomib

Oncotarget6www.impactjournals.com/oncotarget

Figure 4: Selinexor promotes NFκB-IκBα binding. A. Proximity ligation assay for 8226B25 PI-resistant MM cells (3x106/ml) treated and stained with antibodies for NFκB and IκBα. Selinexor (KPT-330) in combination with BTZ increased proximity co-localization of NFκB and IκBα up to 12-fold over untreated and single-agent BTZ or selinexor. Green fluorescence denotes the cytoplasm, and blue indicates the nucleus (DAPI). B. Selinexor/BTZ significantly increased the number of NFκB-IκBα foci in the nucleus versus no drug or single-agent selinexor or BTZ (P ≤ 0.00077) (n=3, 50 cells per assay). Inset: Selinexor treatment did not affect XPO1 protein expression at 4 hours as shown by Western blot.

Figure 5: Immunofluorescence microscopy and Western blot of IκBα in PI-resistant MM cell lines. A/B. Immunofluorescence microscopy, U266PSR (A) and 8226B25 (B) PI-resistant cells showed an increase in IκBα (red) after treatment with selinexor/BTZ compared with untreated control or single-agent BTZ or selinexor. C/D. Selinexor/BTZ combination treatment increased IκBα protein in U266PSR (331%) and 8226B25 (312%) cells compared with untreated control or single-agent BTZ or selinexor (n=4).

Selinexor + Bortezomib promotes NFκB-IκBα binding

Selinexor + bortezomib significantly increases nuclear NFκB-IκBα vs. selinexor or bortezomib.

(Turner 2016, Oncotarget)

0.001 0.01 0.1 1 100

50

100

150 MM.1SOPM2KMS11JJN3H929

KPT330 (µM)

% V

iabilit

y


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PreclinicalAc.vity:Selinexor+Bortezomib

§  Selinexor in combination with bortezomib significantly reduced MM tumor growth in the PI-resistant U226PSR tumor xenograft

(Turner 2016, Oncotarget)


§  Primary Objective: Determine the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D)

§  Patient Populations: §  Arm SVd: selinexor + bortezomib + dexamethasone

§  MM patients relapsing after ≥ 1 prior therapy may include prior bortezomib, as long as not refractory to bortezomib in their most recent line of therapy

§  Arm SPd: selinexor + pomalidomide + dexamethasone (ASH 2016 - Poster 3330)

§  Arm SLd: selinexor + lenalidomide + dexamethasone §  Dosing Scheme SVd: A standard 3 + 3 design will be used for dose escalations:

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SelinexorandbackboneTreatmentsOfmul/pleMyelomaPa/ents:STOMPStudyDesign

Drug Selinexor Once Weekly (QW)

Selinexor Twice Weekly (BIW)

Selinexor, oral Dose Level 1: 80 mg

Dose Level 2: 100 mg

Dose Level 1: 60 mg

Dose Level 2: 80 mg

Bortezomib, SC 1.3 mg/m2 QW/BIW 1.3 mg/m2 QW

Dexamethasone, oral 40 mg QW 20 mg BIW

Expansion at RP2D ~20 patients to be enrolled

QW

Dose Escalation

BIW


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STOMP–SVdPa.entCharacteris.cs

SVd Patient Characteristics N

Patients Enrolled as of November 1, 2016 33

Escalation Patients : Expansion Patients 22 : 11

Median Age, Years (range) 63 (43 – 74)

Males : Females 19 M : 14 F

High Risk Cytogenetics (del17p, t(4;14), t(14;16)) 9 (27%)

Median Prior Regimens (range) -Prior Proteasome Inhibitor -Refractory to Prior Proteasome Inhibitor -Refractory to Prior IMiD (Lenalidomide or Pomalidomide) -Refractory to Prior Lenalidomide and Pomalidomide

4 (1 – 11) 30 (91%) 24 (73%) 30 (91%) 13 (39%)


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TreatmentRelatedAdverseEvents≥10%AE Term

Gastrointestinal Grade 1/2 Grade 3 Grade 4 Total Grade 1/2 Grade 3 Grade 4 Total Grade 1/2 Grade 3 Grade 4 Total Grade 1/2 Grade 3 Grade 4 Total

Anorexia 56% 11% -- 67% 25% -- -- 25% 33% -- -- 33% 33% -- -- 33%

Diarrhea 11% 22% -- 33% 25% -- -- 25% 100% -- -- 100% -- 17% -- 17%

Nausea 22% 11% -- 33% 25% -- -- 25% 67% -- -- 67% 67% -- -- 67%

Vomiting 11% 11% -- 22% 25% -- -- 25% 33% -- -- 33% 33% -- -- 33%

Altered Taste 11% -- -- 11% -- -- -- -- -- -- -- -- 17% -- -- 17%

Constitutional

Weight Loss 44% -- -- 44% -- -- -- -- -- -- -- -- -- -- -- --

Fatigue 56% -- -- 56% 25% -- -- 25% 67% -- -- 67% 50% 17% -- 67%

Dehydration -- -- -- -- 25% -- -- 25% 33% -- -- 33% -- -- -- --

Hematologic

Thrombocytopenia -- 33% 33% 67% 25% 25% 25% 75% -- -- 67% 67% -- 17% -- 17%

Neutropenia -- 33% -- 33% -- -- -- -- -- 33% 33% 67% -- -- -- --

Anemia -- 33% -- 33% -- -- -- -- 33% 33% -- 67% 17% -- -- 17%

Other

Cognitive Disorder -- 22% -- 22% -- -- -- -- -- -- -- -- -- -- -- --

Epistaxis 11% -- -- 11% -- -- -- -- 33% -- -- 33% -- -- -- --

Vision blurred 11% -- -- 11% -- -- -- -- -- -- -- -- 17% -- -- 17%

100 mg Sel QW + 1.3 mg/m2 Bort QW N=6

60/80 mg Sel BIW + 1.3 mg/m2 Bort QW N=9

80 mg Sel QW + 1.3 mg/m2 Bort QW N=4

80 mg Sel QW + 1.3 mg/m2 Bort BIW N=3


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Category N ORR (%)

CBR (%)

sCR (%)

CR (%)

VGPR (%)

PR (%)

MR (%)

SD (%)

PD (%)

Overall 22 17 (77%)

20 (91%)

1 (5%)

2 (9%)

4 (18%)

10 (45%)

3 (14%)

1 (5%)

1 (5%)

PI Refractory 15 10

(67%) 13

(87%) 1

(7%) 1

(7%) 2

(13%) 6

(40%) 3

(20%) 1

(7%) 1

(7%)

PI Non-Refractory* 7 7

(100%) 7

(100%) -- 1 (14%)

2 (29%)

4 (57%) -- -- --

Responses as of November 30, 2016, according to IMWG criteria. ORR=Overall Response Rate (sCR+CR+VGPR+PR), CBR=Clinical Benefit Rate (sCR+CR+VGPR+PR+MR), sCR=Stringent Complete Response, CR=Complete Response, VGPR=Very Good Partial Response, PR=Partial Response, MR=Minor Response, SD=Stable Disease, PD=Progressive Disease

SVdEfficacy–PhaseI

*closest to population to be enrolled in BOSTON Study


45% 40%

57%

40%50% 50%

18%

13%

29%

30% 8%

33%9%

7%

14%

10%

8%

17%

5%

7%8%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

AllPa1ents(N=22) PIRefractory(N=15)

PINon-Refractory(N=7)

PriorTherapies1-3(N=10)

PriorTherapies≥4(N=12)

PINon-Refractory&1-3Priors(N=6)

sCR CR VGPR PR

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SVdORREfficacy:SubGroups–PhaseI

ORR67%

ORR77%

ORR100% ORR100%

ORR80%ORR74%


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TimeonStudyandDura.onofResponseamongResponders–PhaseIPriorP

IStatus

§  MedianDura.onofResponse:7.8months

0 1 2 3 4 5 6 7 8 9 10 11 12

RefRefRefRefRefRefRefRefRefRefRefRefNaïExRefNaïRefExNaïExRefEx

MonthsFollowingIni@a@onofSVdTreatment

Par@alResponse

StringentCompleteResponse

OnStudy

OffStudy

PRPR

PR

PR

PR

PRPR

PR

PR

PR

PRPR

VGPR

PR CR sCR

PD

SD

CR

VGPR CR

VGPRVGPR

VGPR

VGPR

MinorResponse

MR

MRMR

CompleteResponse

VeryGoodPar@alResponse

MR

MR

PR

MonthsFollowingIni.a.onofSVdTreatment

Ref – Refractory Exp – Exposed Naï – Naïve


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ChangeinM-ProteinfromBaseline–PhaseI

§  The majority of patients had reductions in M-Protein from baseline §  18 patients (82%) had reductions >50% §  8 patients (36%) had reductions ≥90%

Ref – Refractory Exp – Exposed Naï – Naïve

Ref Ref Ref Ref Ex Ref Ref Ref Ref Ref Naï Naï Ref Ref Naï Ex Ex Ref Ref Ex Ref Ref

-100

-80

-60

-40

-20

0

20

40

60

80

100

Prior PI Status

Max

imal

tum

or v

olum

e Δ

(%)

SVd: Maximal M-Protein Effect


100 mg oral selinexor QW + 1.3 mg/m2 bortezomib SC QW x 4 / 5 +

40 mg dexamethasone QW

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TreatmentRelatedAEsatRP2D

§  Good tolerability with clear anti-MM activity with once weekly selinexor in combination with once weekly Velcade

§  Considering prolonged tolerability and efficacy across all cohorts, the RP2D is:

AE Term

Gastrointestinal Grade 1 Grade 2 Grade 3 Grade 4 Total

Nausea 24% 35% -- -- 59%

Anorexia 35% 6% -- -- 41%

Vomiting 29% 6% -- -- 35%

Diarrhea 18% -- 6% -- 24%

Altered Taste 6% 6% -- -- 12%

Constitutional

Fatigue 18% 12% 6% -- 35%

Hematologic

Thrombocytopenia -- -- 6% 12% 18%

Other

Abdominal Pain 6% -- 6% -- 12%

100 mg Sel QW + 1.3 mg/m2 Bort QW RP2D Patients (N=17)


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§  Expansion will enroll 20 patients

§  11 patients have been enrolled (10 evaluable for efficacy)

§  Median time on study: 3 cycles (range <2 – 4 cycles)

§  9 out of 10 patients remain on treatment

ExpansionPa.ents–SpiderPlot

0%

20%

40%

60%

80%

100%

120%

C1D1 C2D1 C3D1 C4D1

Percen

tCha

ngeinM

-ProteinFromBaseline

PR

PINon-RefractoryPa.ents

PIRefractoryPa.ents

PR

PR

MRMR

SD

SDSD

SD

SD


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§  Selinexor in combination with bortezomib and low dose dexamethasone (SVd) is well tolerated with low rates of major adverse events §  Minimal clinically significant overlapping toxicity §  AEs were manageable (predominantly G1/2) and included nausea, fatigue, anorexia,

and thrombocytopenia (mostly G3/4).

§  SVd has potent activity in patients with heavily pretreated multiple myeloma, including those with proteasome inhibitor (PI)-refractory disease and ≥4 lines of therapy: §  ORR 77% overall, 67% in PI-refractory disease, and 100% in PI-non-refractory MM

§  The recommended SVd phase II dose: §  weekly PO selinexor 100 mg, sc bortezomib 1.3 mg/m2 and PO dexamethasone 40 mg §  Convenient, cost-effective and highly potent anti-MM regimen §  Phase 3 Randomized BOSTON Study of SVd vs. Vd to begin in early 2017

Conclusions

selinexor in combinaon with bortezomib and dexamethasone … · 2019. 5. 8. · ash 58th annual...

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