Selinexor Demonstrates Marked Synergy with Dexamethasone (Sel-Dex) in Preclinical Models and in Patients with Heavily Pretreated Refractory Multiple Myeloma (MM)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4773-4773 ◽  
Author(s):  
Christine I. Chen ◽  
Martin Gutierrez ◽  
David S. Siegel ◽  
Joshua R. Richter ◽  
Nina Wagner-Johnston ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Transcriptional Activation ◽  
Nuclear Export ◽  
Research Funding ◽  
Phase 1 ◽  
Advisory Committees ◽  
Nuclear Retention ◽  
Heavily Pretreated ◽  
Equity Ownership

Abstract Introduction: The nuclear export protein exportin 1, (XPO1) is overexpressed in a wide variety of cancers including MM and often correlate with poor prognosis. Selinexor (KPT-330) is an oral Selective Inhibitor of Nuclear Export (SINE) XPO1 antagonist in Phase 1 and 2 clinical studies. Selinexor forces nuclear retention and reactivation of tumor suppressor proteins (TSPs) and reduction of many proto-oncogenes, including MDM2, MYC and Cyclin D. In addition, selinexor potently deactivates NF-κB, through forced nuclear retention of IκBα. Together these effects induce selective apoptosis in MM cells and inhibition of NF-κB dependent osteoclast activation. XPO1 is also responsible for nuclear export of the glucocorticoid receptor (GR). We hypothesized that selinexor will enhance the activity of dexamethasone (DEX)-bound GR, resulting in synergistic tumor cell killing. Methods: In vitro tumor cell viability measurements were based on MTT (CellTiter 96¨/Promega) and combination indices were calculated using CalcuSyn software. For xenograft studies, utilized NOD-SCID mice with subcutaneous inoculation of MM.1s cells. GR nuclear localization was measured with immunofluorescent anti-GR (phosphor-S211) antibody and quantitative imaging. To assess GR transcriptional activation, GR binding to a GCR consensus sequence was measured in nuclear extracts using an ELISA method (GR ELISA kit/Affymetrix). Patients (pts) with heavily pretreated refractory MM were dosed with oral selinexor at doses of up to 60 mg/m2 (8-10 doses/4 wk cycle) as part of a Phase 1 program in advanced hematological malignancies. Response we defined based on the IMWG criteria. The effect of combining DEX with selinexor was analyzed in all pts who received selinexor at moderate to high doses (30-60 mg/m2). Safety and efficacy were analyzed separately in three groups: no DEX, <20 mg DEX and 20 mgs DEX. Results: In MM.1s cells Sel-Dex showed synergy for nuclear retention of the DEX activated GR (Ser211-phosphorylated) and concomitant GR transcriptional activation. Sel-Dex showed highly synergistic cytotoxicity in MM.1s cells in vitro and in vivo, with a corresponding increase in apoptosis. Selinexor alone was potently cytotoxic in the DEX resistant MM cell lines MM.1R and ANBL6, but addition of DEX provided no additional effect. Twenty-eight pts with heavily pretreated refractory MM (16 M, 12 F; median age 62; ECOG PS 0/1: 7/21; median prior regimens: 6) received selinexor at 30 – 60 mg/m2 with either 0, <20, or 20 mgs DEX. All pts have received a proteasome inhibitor and an Imid and the majority of the pts have received pomalidomide (68%) and/or carfilzomib (36%). The most common Grade 1/2 AEs for these three groups were: nausea (82%/86%/70%), fatigue (55%/86%/40%), anorexia (36%/71%/60%), and vomiting (36%/57%/10%). Of the 28 pts treated; 10 heavily pretreated refractory MM pts treated with a combination of selinexor (45 mg/m2 twice weekly) and DEX (20 mg with each selinexor dose) were found to have dramatically improved disease response (n=10, ORR 60%), with one stringent complete response (sCR, 10%), 5 partial responses (PR, 50%) and clinical benefit rate (CBR) rate of 80% (Figure 1). Treatment with ³30mg/m2 selinexor and <20 mg DEX (n=7), resulted in ORR of 14% and CBR of 86%, while treatment with selinexor (30-60 mg/m2) without DEX (n=12) showed best response of stable disease (50%). Sel-Dex was also associated with an increase in time on study relative to selinexor alone, with 7 of out 10 pts in the 20 mg DEX combo group still on study (11-25 weeks). Five additional pts were treated with selinexor at a dose of 60 mg/m2 in combination with 20 mg DEX. Response evaluation is pending. Conclusions: Sel-Dex combination is markedly synergistic in preclinical models, which is supported by the preliminary clinical data presented. One potential mechanism underlying this synergy is the amplification of GR activity due the combined effects of selinexor-induced nuclear retention of activated GR coupled with DEX-mediated GR agonism. These results provide a promising basis for the continuing study of Sel-Dex for treatment of pts with refractory MM. Phase 2 studies of Sel-Dex in pts with MM refractory to both pomalidomide and carfilzomib are planned for early 2015. Disclosures Chen: Celgene: Honoraria; Janssen: Honoraria. Off Label Use: Lenalidomide maintenance therapy after ASCT. Gutierrez:Senesco: PI Other. Siegel:Celgene, Millennium, Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Baz:Celgene: Research Funding; Millennium: Research Funding; Bristol Myers Squibb: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding. Kukreti:Celgene: Honoraria. Azmi:Karyopharm Therpeutics: Research Funding. Kashyap:Karyopharm Therapeutics: Employment. Landesman:Karyopharm Therapeutics: Employment. Marshall:Karyopharm Therpeutics: Employment. McCartney:Karyopharm Therpeutics: Employment. Saint-Martin:Karyopharm Therpeutics: Employment. Norori:Karyopharm Therpeutics: Consultancy. Savona:Karyopharm Therpeutics: Membership on an entity's Board of Directors or advisory committees. Rashal:Karyopharm Therapeutics: Employment. Carlson:Karyopharm Therapeutics: Employment. Mirza:Karyopharm Therpeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Shacham:Karyopharm Therapeutics Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Kauffman:Karyopharm Therapeutics: Employment, Equity Ownership. Reece:Millennium: Honoraria, Research Funding; Millennium: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Merck: Research Funding; Merck: Research Funding; BMS: Research Funding; BMS: Research Funding; Novartis: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Amgen : Honoraria; Amgen : Honoraria.

The Oral Selective Inhibitor of Nuclear Export (SINE) Selinexor (KPT-330) Demonstrates Broad and Durable Clinical Activity in Relapsed / Refractory Non Hodgkin’s Lymphoma (NHL)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 396-396 ◽  
Author(s):  
John Kuruvilla ◽  
John C. Byrd ◽  
Joseph M Flynn ◽  
Ramiro Garzon ◽  
Pierluigi Porcu ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Nuclear Export ◽  
Research Funding ◽  
Phase 1 ◽  
Single Agent ◽  
Objective Response ◽  
Employment Equity ◽  
Advisory Committees ◽  
Heavily Pretreated ◽  
Equity Ownership

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. Abstract 396. Table 1 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 Disclosures 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.

A Phase 1/2 Study of the Second Generation Selective Inhibitor of Nuclear Export (SINE) Compound, KPT-8602, in Patients with Relapsed Refractory Multiple Myeloma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4509-4509 ◽  
Author(s):  
R. Frank Cornell ◽  
Adriana C Rossi ◽  
Rachid Baz ◽  
Craig C Hofmeister ◽  
Chaim Shustik ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Board Of Directors ◽  
Nuclear Export ◽  
Research Funding ◽  
Low Dose ◽  
Phase 1 ◽  
Single Agent ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Abstract Introduction - Inhibition of Exportin 1 (XPO1) is a novel treatment approach for multiple myeloma (MM). XPO1 mediates the nuclear export of cell-cycle regulators and tumor suppressor proteins leading to their functional inactivation. In addition, XPO1 promotes the export and translation of the mRNA of key oncoproteins (e.g. c-MYC, BCL-2, Cyclin D). XPO1 overexpression occurs in solid and hematological malignancies, including MM and is essential for MM cell survival. Selinexor, the first oral SINE compound, has shown promising anti-MM activity in phase 1 studies but has been associated with gastrointestinal and constitutional toxicities including nausea, anorexia and fatigue. KPT-8602 is a second generation oral SINE compound with similar in vitro potency to selinexor, however, has substantially reduced brain penetration compared with selinexor, and demonstrated markedly improved tolerability with minimal anorexia and weight loss in preclinical toxicology studies. In murine models of MM, KPT-8602 can be dosed daily (QDx5) with minimal anorexia and weight loss. We have therefore initiated a phase 1/2 first-in-human clinical trial. Methods - This phase 1/2 clinical trial was designed to evaluate KPT-8602 as a single agent and in combination with low dose dexamethasone (dex) in patients (pts) with relapsed / refractory MM (RRMM). KPT-8602 is dosed orally (QDx5) for a 28-day cycle with a starting dose of 5 mg. Low dose dex (20 mg, twice weekly) is allowed after cycle 1 if at least a minimal response (MR) is not observed. The primary objective is to evaluate the safety and tolerability including dose-limiting toxicity (DLT), determine the maximum tolerated dose (MTD), the recommended Phase 2 dose (RP2D), and evidence for anti-MM activity for KPT-8602 single agent and in combination with dex. The pharmacokinetic (PK) and pharmacodynamic (PDn; XPO1 mRNA) profile of KPT-8602 will also be determined. PDn predictive biomarker analysis and ex vivo drug response assays are underway using tumor cells from bone marrow aspirates before treatment, during and at relapse. These analyses include cell death pathway assays by flow and nuclear/cytoplasmic localization of XPO1, NF-ƙB, IƙBα, IKKα, NRIF and p53 by imaging flow and IHC. Results - As of 01-Aug-2016, 6 pts 2 M/4 F, (median of 6 prior treatment regimens, median age of 71) with RRMM have been enrolled. Common related grade 1/2 adverse events (AEs) include thrombocytopenia (3 pts), nausea (2 pts) and diarrhea (2 pts). Grade 3 AEs include neutropenia (1 pt) and dehydration (1 pt). No grade 4 or 5 AEs have been reported. No DLTs have been observed and the MTD has not been reached. 5 pts were evaluable for responses (1 pt pending evaluation): 1 partial response, 1 minimal response, and 3 stable disease; no pts have progressed on therapy with the longest on for >5 months. The PK properties following oral administration showed that 5 mg of KPT-8602 was rapidly absorbed (mean tmax= 1 hr, mean Cmax= 30.6 ng/mL). The mean AUCinf was calculated to be 141 ng•hr/mL. After tmax, KPT-8602 declined at an estimated mean t½ of 4 hr. At the same dose level, XPO1 mRNA expression was the highest (~2.5 fold) at 8 hr post dose. Conclusions - Oral KPT-8602 is well tolerated in heavily pretreated pts with RRMM. Gastrointestinal and constitutional toxicities observed with twice weekly selinexor have not been observed with 5x/week KPT-8602, including in pts on study for >4 months. PK was predictable and in line with selinexor. These early results show encouraging disease control with pts remaining on therapy. Enrollment is on-going. Disclosures Rossi: Takeda: Speakers Bureau; Janssen: Speakers Bureau; Onyx: Research Funding, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Baz:Takeda/Millennium: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Signal Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Merck: Research Funding; Novartis: Research Funding. Hofmeister:Karyopharm Therapeutics: Research Funding; Arno Therapeutics, Inc.: Research Funding; Signal Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees; Janssen: Pharmaceutical Companies of Johnson & Johnson: Research Funding; Incyte, Corp: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Takeda Pharmaceutical Company: Research Funding; Teva: Membership on an entity's Board of Directors or advisory committees. Shustik:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Richter:Amgen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Jannsen: Speakers Bureau. Chen:Janssen: Honoraria, Research Funding; Takeda: Research Funding; Celgene: Honoraria, Research Funding. Vogl:Takeda: Consultancy, Research Funding; Celgene: Consultancy; GSK: Research Funding; Calithera: Research Funding; Teva: Consultancy; Karyopharm: Consultancy; Acetylon: Research Funding; Constellation: Research Funding. Shacham:Karyopharm Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Baloglu:Karyopharm Therapeutics: Employment, Equity Ownership. Senapedis:Karyopharm Therapeutics: Employment, Equity Ownership. Ellis:Karyopharm Therapeutics: Employment, Equity Ownership. Friedlander:Karyopharm Therapeutics: Employment. Choe-Juliak:Karyopharm Therapeutics: Employment. Sullivan:Karyopharm Therapeutics: Research Funding. Kauffman:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Combination of Selinexor and the Proteasome Inhibitor, Bortezomib Shows Synergistic Cytotoxicity in Diffuse Large B-Cells Lymphoma Cells In Vitro and In Vivo

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4131-4131 ◽  
Author(s):  
Trinayan Kashyap ◽  
Irfana Muqbil ◽  
Amro Aboukameel ◽  
Boris Klebanov ◽  
Ramzi Mohammad ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Board Of Directors ◽  
Nuclear Export ◽  
Transcriptional Activity ◽  
Employment Equity ◽  
Advisory Committees ◽  
Nuclear Retention ◽  
Equity Ownership

Abstract Background: XPO1 (exportin-1/CRM1) mediates nuclear export of proteins containing leucine-rich amino-acid consensus sequences. XPO1 cargo proteins include many of the major tumor suppressor proteins (p53, IkB, pRB, FOXOs) and their export leads to the inactivation of cell cycle checkpoints. Overexpression of XPO1 has been reported to correlate with poor cancer prognosis. The Selective Inhibitor of Nuclear Export (SINE) compound, selinexor, binds covalently to the cargo pocket on XPO1, inhibits nuclear export which leads to cell cycle arrest and specific cancer cell death. Selinexor is currently in advanced clinical trials for patients with solid and hematological malignancies including patients with relapsed/refractory Diffuse Large B-Cell Lymphoma (DLBCL) (NCT02227251). Using preclinical models, we recently demonstrated that proteasome inhibitors (PI) can re-sensitize multiple myeloma that acquired resistance to selinexor. Here, we aimed to find if treatment with selinexor and bortezomib is beneficial for the treatment of DLBCL. Methods: DLBCLcell lines were treated with selinexor in combination with bortezomib. Cell viability was examined using standard viability assays after 72 hours of treatment. Whole cell protein lysates were evaluated by immunoblotting. NF-κB transcriptional activity was analyzed using an ELISA assay. WSU-DLCL2 cells were grown as sub-cutaneous tumors in ICR SCID mice. Tumor bearing mice were divided into 4 groups and were administered either vehicle, sub-maximum tolerated doses of selinexor (10 mg/kg p.o. twice a week, M, Th), bortezomib (1 mg/kg i.v. twice a week, M, TH) and the combination of selinexor (10 mg/kg p.o. twice a week) plus bortezomib (1 mg/kg i.v. twice a week). Results: The combination treatment of selinexor with bortezomib synergistically killed DLBCL cells compared to the single agents alone. Co-treatment with bortezomib enhanced selinexor mediated nuclear retention of IκB-α. Selinexor plus bortezomib treatment decreased NF-κB transcriptional activity. Finally, the combination of selinexor with bortezomib showed superior anti-tumor efficacy in the combination group compared to single agent treatments in WSU-DLCL2 xenograft model. Conclusions: Based on our results, inhibition of NF-κB transcriptional activity through forced nuclear retention of IκB appears to be an important mechanism underlying the synergistic effects of selinexor plus bortezomib in many different cell lines including DLBCL. The superior efficacy of selinexor plus bortezomib combination both in vitro and in vivo when compared to single agents along provides a rational for conducting clinical trials with these combinations in DLBCL patients. Disclosures Kashyap: Karyopharm Therapeutics: Employment, Equity Ownership. Klebanov:Karyopharm Therapeutics: Employment, Equity Ownership. Senapedis:Karyopharm Therapeutics: Employment, Equity Ownership. Shacham:Karyopharm Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Kauffman:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Landesman:Karyopharm Therapeutics: Employment, Equity Ownership.

Effects Of Inhibition Of XPO1/CRM1-Dependent Nuclear Export By Selinexor (KPT-330), Alone and In Combination With Carfilzomib (CFZ), On Apoptosis and Autophagy In Multiple Myeloma (MM)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 279-279 ◽  
Author(s):  
Shaun Rosebeck ◽  
Malathi Kandarpa ◽  
Mattina M. Alonge ◽  
Jagoda Jasielec ◽  
Dominik Dytfeld ◽  
...  
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Board Of Directors ◽  
Nuclear Export ◽  
Research Funding ◽  
Proteasome Inhibition ◽  
Employment Equity ◽  
Advisory Committees ◽  
Nuclear Retention ◽  
Equity Ownership

Abstract Introduction Exportin 1 (XPO1/CRM1) is the sole transporter of most tumor suppressor proteins (TSP) from the nucleus to the cytoplasm. Small molecule selective inhibitors of nuclear export (SINE) block XPO1-mediated nuclear export, leading to nuclear retention of TSP, inducing cancer cell death and sensitizing cancer cells to other cytotoxic drugs. Although the cytotoxic and apoptotic effects of SINE on different cancer cells have now been established, the mechanism of cell death is still not fully understood. Recently, autophagy emerged as a possible cell death pathway and alternate to the ubiquitin-proteasome pathway (UPP) by which excess and/or dysfunctional proteins and organelles are degraded and recycled. MM cells require basal autophagy for survival and caspase 10 protease activity is required to limit autophagic cell death. The possibility that autophagy may be involved in the mechanism of action of SINE is supported by observations that knockdown of XPO1 can promote autophagy and that cytoplasmic p53 can repress autophagy. In this study, we evaluated the contribution of autophagy to the effects of Selinexor (KPT-330), a SINE currently in two phase I clinical trials, on MM cell cytotoxicity. Because proteasome inhibition can also induce autophagy, we hypothesized that the combination of Selinexor and CFZ, a next generation irreversible proteasome inhibitor approved for treatment of MM, may synergistically augment cytotoxicity in MM cells. Methods Plasma cells (PC) were purified from consented MM patient bone marrow aspirates using EasySep (Stem Cell Technology). PC purity (>80%) was determined by Wright-Giemsa staining of cytospins. Human myeloma cell lines (HMCL) NCI-H929, RPMI-8226, MM1.S and MM1.R were cultured in RPMI1640 with 10% FBS. IC50 values were determined using GraphPad Prism. Drug combination efficacy was determined using CalcuSyn (Biosoft). Combination index (CI) values <1.0 indicate synergy. Transcription factor profiling plate array II was from Signosis (Sunnyvale, CA). Otherwise, our studies used standard cellular and molecular biology techniques. Results Selinexor caused significant cytotoxicity in HMCL (IC50 10-100 nM), induced cell cycle arrest in G1, and promoted apoptotic cell death typified by caspase activation, DNA fragmentation, and Annexin V binding. Importantly, purified PC from newly-diagnosed MM patients were also sensitive to the cytotoxic effects of Selinexor. HMCL treated with KPT-330 also exhibited nuclear retention of p53. To gain insight into more global effects of SINE treatment, we assayed DNA binding activity of approx. 100 different transcription factors. TSP, such as Rb, p53, and EGR-1, exhibited increased activity, whereas proto-oncogenes, including NF-κB, Myc, and Myb, were inactivated in response to KPT-330. Western blot analysis of inactivated targets showed nearly total loss of protein. Unlike XPO1, which is degraded via the UPP upon treatment with SINE, loss of Myc and NF-κB subunits, including RelA, RelB, and p52, could not be reversed by proteasome inhibition. Instead, we found that Selinexor treatment induced markers of autophagy, including LC3B induction and processing, and promoted loss of caspase 10, which is associated with autophagic cell death in MM. Importantly, we have determined that the combination of Selinexor and CFZ results in synergistic cell death (CI 0.2-0.6) characterized by enhanced induction of both apoptosis and autophagy in HMCL. The effects of Selinexor and CFZ were also evaluated in NOD-SCID mice inoculated subcutaneously with NCI-H929 cells. Mice were treated 3 times weekly per oswith Selinexor (5 or 10 mg/kg) alone and in combination with twice-weekly IV-administered CFZ (1.5 or 3 mg/kg). After 16 days of treatment, high doses of either CFZ or Selinexor alone moderately inhibit tumor growth. Treatment with the combination of CFZ and Selinexor at all dose levels was more effective than single agent treatment, and high dose combination treatment completely impaired xenograft tumor growth with good tolerability. Conclusion Our studies are the first to suggest that Selinexor-induced cell death correlates with both apoptosis and autophagy, and that both cell death pathways are enhanced in response to combined treatment with CFZ. Overall, our pre-clinical study provides strong rationale for evaluation of Selinexor in combination with CFZ for the treatment of MM. Disclosures: McCauley: Karyopharm Therapeutics Inc.: Employment, Equity Ownership, Patents & Royalties. Shacham:Karyopharm Therapeutics Inc.: Employment, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Patents & Royalties. Kauffman:Karyopharm Therapeutics Inc.: Employment, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Patents & Royalties. Jakubowiak:BMS: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Millennium: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Onyx: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau.

scholarly journals Deep and Durable Responses with Selinexor, Daratumumab, and Dexamethasome (SDd) in Patients with Multiple Myeloma (MM) Previously Exposed to Proteasome Inhibitors and Immunomodulatory Drugs: Results of Phase 1b Study of SDd

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 599-599 ◽  
Author(s):  
Cristina J Gasparetto ◽  
Suzanne Lentzsch ◽  
Gary J. Schiller ◽  
William Bensinger ◽  
Nizar Bahlis ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Nuclear Export ◽  
Research Funding ◽  
Phase 1 ◽  
Proteasome Inhibitors ◽  
Maximum Tolerated Dose ◽  
Immunomodulatory Drugs ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Abstract Introduction - Selinexor is a first-in-class Selective Inhibitor of Nuclear Export (SINE) compound that binds and inactivates Exportin 1 (XPO1). Selinexor with low dose dexamethasone (Sd) or in with protesome inhibitors (PIs) or immunomodulatory drugs (IMiDs), has shown anti-MM activity in patients (pts) with relapsed or refractory MM. Daratumumab (Dara), an anti-CD38 mAb, is approved for the treatment of heavily pretreated MM is limited by short PFS and an ORR of ~21% in quad-refractory MM. Selinexor in combiniation with dara have shown preclinical synergistic killing of MM cells. Methods - Pts were eligible if they had received ≥ 3 prior lines of anti-myeloma therapy, including a PI and an IMiD. Selinexor was dose-escalated in 2 concurrent cohorts: once-weekly (QW, at 100 mg) or twice-weekly (BIW, at 60 mg). Dara was 16 mg/kg IV (recommended schedule) and dexamethasone (dex) was 40 mg QW or 20 mg BIW. The objectives were to determine the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), safety, tolerability and preliminary efficacy of the combination of this SDd combination in pts with PI/IMiD refractory MM Results - As of Jul 20th2018, 25 pts (11 males / 14 females) have been enrolled. Three pts have been enrolled into the 60 mg BIW and 22 pts in the 100 mg QW cohorts. Pts have a median age of 68 years and a median of 3 (range, 2 - 10) prior treatment regimens. Common SDd treatment related adverse events included (all grades, grades 3/4): thrombocytopenia (58%, 42%), leukopenia (54%, 38%), anemia (46%, 29%), nausea (50%, 0%) and fatigue (46%, 8%). Two dose limiting toxicities (DLTs) were reported in the 60 mg BIW cohort: G3 thrombocytopenia and G2 fatigue requiring dose reduction in selinexor to 100 mg QW. In the 100 mg QW escalation cohort, 6 pts enrolled, 5 evaluable, with no DLTs. This cohort was expanded and enrollment is ongoing. A total of 21 pts were evaluable for response. In 19 dara-naïve pts, the ORR was 74% (5 VGPR, 9 PR, 2 MR, 2 SD, 1 PD), including 3 unconfirmed PRs, 1 unconfirmed MR. In the 2 pts with dara refractory MM, there was one PD and one SD. The longest duration of therapy is 13 months. Based on tolerability and efficacy, the RP2D of SDd is selinexor 100 mg, daratumumab 16 mg/kg and dex 40 mg, administered QW. Conclusions - Selinexor 100 mg QW can be combined safely with dara (per approved dosing) and dex. The preliminary ORR of 74% with SDd in patients with PI/IMiD refractory MM who are dara naïve is promising and compares favorably to 21% ORR of Dara and Sd in quad refractory myeloma. This once weekly regimen is well tolerated with no major organ toxicities to date. Data from the full phase 1 dose expansion will be presented. Disclosures Gasparetto: Takeda: Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel; Janssen: Consultancy, Honoraria, Other: Travel; Celgene: Consultancy, Honoraria, Other: Travel, Research Funding. Schiller:Celator/Jazz Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding. Bensinger:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; amgen: Speakers Bureau; Takeda: Speakers Bureau. Bahlis:Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria. White:Amgen, Celgene, Janssen, Takeda: Honoraria. Sebag:Amgen Canada: Membership on an entity's Board of Directors or advisory committees; Takeda Canada: Membership on an entity's Board of Directors or advisory committees; Janssen Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene Canada: Membership on an entity's Board of Directors or advisory committees. Venner:Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria; Takeda: Honoraria. Leblanc:Janssen Inc.: Membership on an entity's Board of Directors or advisory committees; Amgen Canada: Membership on an entity's Board of Directors or advisory committees; Celgene Canada: Membership on an entity's Board of Directors or advisory committees; Takeda Canada: Membership on an entity's Board of Directors or advisory committees. Chen:Amgen: Honoraria. Shah:Karyopharm Therapeutics: Employment. Jeha:Karyopharm Therapeutics: Employment. Saint-Martin:Karyopharm Therapeutics: Employment. Kauffman:Karyopharm Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Shacham:Karyopharm Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Lipe:Celgene: Consultancy.

Safety, Efficacy, and Determination of the Recommended Phase 2 Dose for the Oral Selective Inhibitor of Nuclear Export (SINE) Selinexor (KPT-330)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 258-258 ◽  
Author(s):  
Christine Chen ◽  
Ramiro Garzon ◽  
Martin Gutierrez ◽  
Meagan A. Jacoby ◽  
Peter Brown ◽  
...  
Keyword(s):  
Nuclear Export ◽  
Research Funding ◽  
Hematological Malignancies ◽  
Phase 1 ◽  
High Grade ◽  
Nuclear Retention ◽  
Flat Dose ◽  
Heavily Pretreated ◽  
Equity Ownership ◽  
Grade 3

Abstract Background: The nuclear export protein XPO1 is overexpressed in all types of hematological malignancies. The SINE selinexor (KPT-330) is a novel, first-in-class, slowly reversible XPO1 antagonist that forces the nuclear retention and activation of over tumor suppressor proteins (TSPs) such as p53, IkB, FOXO and p21. Forced nuclear retention of TSPs leads to their reactivation, which can counteract a multitude of oncogenic pathways that perpetuate the neoplastic phenotype. In addition, XPO1 inhibition prevents the eIF4e-mediated export of messenger mRNA for a variety of oncoproteins (FLT3, c-KIT, cyclin D1, c-MYC, Bcl2), leading to decreased expressed to further provide anti-cancer activity. An ongoing Phase 1 (NCT01607892) open label, dose escalation, multi-center study in hematological malignancies was designed to evaluate the safety and tolerability of selinexor as well as response rate as the secondary objective. A maximum tolerated dose (MTD) was not identified yet in this study, but based on the ongoing Phase1 study of selinexor in pts with solid tumors, a MTD of 65 mg/m2 twice weekly was determined. The goal of the analyses reported here was to identify the recommended Phase 2 dose (RP2D) based on both tolerability and efficacy in patients with heavily pretreated hematological malignancies. Methods: A subset (N=157) of the Phase 1 patient population received oral selinexor twice weekly (8 doses/28-d cycle). General clinical observations suggested that doses of selinexor >35 mg/m2 (> ~60 mg flat dose) are associated with suboptimal tolerability. Therefore, based on the actual dose administered, patients were divided into groups receiving 45-65 mg (median 60 mg; N=59) and >65 mg (70-160 mg; median 90 mg, N=98) for comparison of safety and efficacy endpoints. The majority of the patients have heavily pretreated myeloma, NHL, and AML. Results: 157 pts received 45-160 mg selinexor twice weekly (89 M/68 F, median age 66 yr; median 4 prior regimens). The most common adverse events (AEs) were fatigue (66%), nausea (64%), anorexia (55%), vomiting (38%), which were mostly gr 1/2, and thrombocytopenia (44%), which was mostly grade 3/4. Incidence of certain selinexor-related high grade (3/4) adverse events was greater in pts receiving >65 mg selinexor vs those receiving 45-65 mg (Table 1). Grade 3 nausea (4%), anorexia (3%), vomiting (3%) and hypokalemia (3%) were observed in the >65 mg group but were not seen in the 45-65 mg group. Grade 3 and 4 anemia were 19% vs 14% and 4% vs 2% for the >65 mg vs 45-65 mg groups, respectively. Grade 3 and 4 thrombocytopenia was similar in both groups, but slightly higher in the >65 mg group, with 8% and 24 % in the 45-65 mg group vs 12% and 27% in the >65 mg group. Neutropenia was also very similar in Grade 3 and 4 toxicity for both groups with 10% and 12% in the 45-65 mg group vs 11% and 10% in the >65 mg group. In contrast, high grade cataract was only seen in the 45-65 mg group (8%; 3 gr 3, 1 gr 4). Selinexor-induced weight loss, as compared to baseline, was maximal by the end of cycle 2 in both dose groups, without further loss through at least cycle 4, but the >65 mg group lost on average >5-fold more weight (average of 3.8 ± 1.1 kg vs 0.7 ± 0.1 kg in the 65 mg group from 56 d- 126 d; p<0.001). Also, pts in the 45-65 mg group remained on study longer (average of 101 d vs 69 d in the >65 mg group; p=0. 05). In contrast, overall efficacy in the two dose groups was comparable, with 5 complete responses (CRs, 10%) and an overall response rate (ORR) of 23% in the 45-65 mg group and 4 CRs (5%) and ORR of 24% in the >65 mg group. A listing of all responses for both groups can be seen in Table 2. Conclusions: While efficacy is comparable, doses of selinexor from 45-65 mg (median 60 mg) are better tolerated than doses >65 mg, based upon decreased weight loss, incidence of high grade AEs, and greater numbers of days on study. Based on this superior risk-benefit, a flat dose of 60 mg selinexor, twice weekly, is the RP2D for patients with hematological cancers. Similar results have been observed for solid tumors. Disclosures Chen: Celgene: Consultancy, Honoraria, Research Funding. Jacoby:Novo Nordisk: Consultancy; Sunesis: Research Funding. Stone:AROG: Consultancy; Celator: Consultancy; Novartis: Research Funding; Pfizer: Consultancy; Juno: Consultancy; Celgene: Consultancy; Karyopharm: Consultancy; Amgen: Consultancy; Agios: Consultancy; Roche/Genetech: Consultancy; Abbvie: Consultancy; Sunesis: Consultancy, Other: DSMB for clinical trial; Merck: Consultancy. Baz:Sanofi: Research Funding; Celgene Corporation: Research Funding; Karyopharm: Research Funding; Millennium: Research Funding. Gabrail:Sanofi: Honoraria, Speakers Bureau; Janssen: Speakers Bureau; BI: Honoraria, Speakers Bureau; Onyx: Honoraria, Speakers Bureau. Wang:Celgene: Research Funding. Martin:Janssen: Consultancy, Honoraria; Acerta: Consultancy; Gilead: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Bayer: Consultancy. Siegel:Celgene Corporation: Consultancy, Speakers Bureau; Amgen: Speakers Bureau; Takeda: Speakers Bureau; Novartis: Speakers Bureau; Merck: Speakers Bureau. Marshall:Karyopharm: Employment. Saint-Martin:Karyopharm: Employment. Carlson:Karyopharm: Employment. Shacham:Karyopharm: Employment, Equity Ownership. Kauffman:Karyopharm: Employment, Equity Ownership. Kuruvilla:Gilead: Consultancy; Hoffmann LaRoche: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Merck: Honoraria; Bristol-Myers Squibb: Honoraria; Lundbeck: Honoraria; Karyopharm: Honoraria.

scholarly journals A Phase 1/2 Trial of TH-302 and Dexamethasone without or with Bortezomib (TBorD) in Patients with Relapsed/Refractory Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2142-2142
Author(s):  
Jacob P. Laubach ◽  
Noopur S. Raje ◽  
Andrew J. Yee ◽  
Philippe Armand ◽  
Robert L. Schlossman ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Research Funding ◽  
Progressive Disease ◽  
Response Rate ◽  
Phase 1 ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Abstract Background: TH-302 is a 2-nitroimidazole prodrug of the DNA alkylator bromo-isophosphoramide mustard that is selectively activated under hypoxic conditions. TH-302 has demonstrated anti-myeloma activity in preclinical models both in vitro and in vivo, as well as synergistic cytotoxic activity with bortezomib (Bor) in vitro. An ongoing Phase 1/2 study (NCT01522872) investigates TH-302 with dexamethasone (dex) without Bor or with Bor (TBorD) in patients (pts) with relapsed/refractory multiple myeloma (RR MM). The maximum-tolerated dose (MTD) of TH-302 plus dex was previously established at 340 mg/m2. We report preliminary results from pts treated at the MTD of TH-302 plus dex; enrollment in the TBorD arm is ongoing. Methods: The Phase 1/2 open-label multicenter study investigates IV TH-302 (240-480 mg/m²) plus PO dex (40 mg) with or without Bor (1.3 mg/m2) on Days 1, 4, 8 and 11 of a 21-day cycle. At the MTDs, Simon two-stage designs are implemented to pursue a regimen of TH-302 plus dex if ≥25% response rate or discontinue if ≤5% (90% power, 10% alpha), and pursue TBorD if ≥50% response rate or discontinue if ≤25% (85% power, 10% alpha). Treatment at the MTD of TH-302 plus dex, and establishment of the MTD of TH-302 in TBorD, is ongoing. Results: 24 pts (19 male, 5 female) with median age 65 years (range: 53 – 86) were enrolled at the 340 mg/m2 MTD of the TH-302 plus dex biweekly regimen. Ten pts had 18 severe adverse events (SAEs), of which 9 were related to TH-302, including 3 pts with cellulitis and 2 pts with pneumonia. Of 17 pts assessable for response at the time of abstract submission, 3 pts achieved a partial response (PR) and 2 pts achieved a minimal response (MR) for an overall response rate of 18% (PR) and a clinical benefit rate of 29% (PR+MR). Nine pts achieved stable disease and 3 pts had progressive disease. Eight pts are undergoing treatment; 16 pts discontinued: progressive disease (10), subject decision (4), AE (1) and alternative therapy (1). The initial dose escalation with TBorD has been completed at 240 mg/m2 TH-302, with enrollment ongoing at 340 mg/m2 TH-302. Conclusions: TH-302 can be administered at 340 mg/m2 biweekly with dex. Preliminary clinical activity has been noted in pts with heavily pre-treated RR MM. Data from the complete cohort of pts treated with dex and initial patients treated with TBorD will be updated and presented at the meeting. Disclosures Laubach: Onyx: Research Funding; Novartis: Research Funding; Millenium: Research Funding; Celgene: Research Funding. Raje:Acetylon: Research Funding; Eli Lilly: Research Funding; Millenium: Consultancy; Celgene: Consultancy; Onyx: Consultancy; Novartis: Consultancy; Amgen: Consultancy. Schlossman:Millennium: Consultancy. Matous:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics: Speakers Bureau. Reynolds:Threshold: Honoraria. Shain:Onyx/Amgen: Research Funding; Celgene: Research Funding; Envision/Celgene: Speakers Bureau; L&M Healthcare/Onyx/Amgen: Speakers Bureau. Zackon:Millenium: Speakers Bureau. Mar:Threshold: Employment. Handisides:Threshold: Employment, Equity Ownership. Kroll:Threshold: Employment, Equity Ownership. Anderson:Celgene: Consultancy; Millenium: Consultancy; Onyx: Consultancy; Gilead: Consultancy; Sanofi Aventis: Consultancy; BMS: Consultancy; Oncopep/Acetylon: Equity Ownership. Richardson:Millenium: Membership on an entity's Board of Directors or advisory committees; JNJ: Membership on an entity's Board of Directors or advisory committees. Ghobrial:Millennium/Takeda: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees.

Preliminary Results of a Phase 2 Study of PD 0332991 in Combination with Bortezomib and Dexamethasone in Patients with Relapsed and Refractory Multiple Myeloma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2940-2940
Author(s):  
Ruben Niesvizky ◽  
Luciano J Costa ◽  
Nisreen A. Haideri ◽  
Georg Hess ◽  
Seema Singhal ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Board Of Directors ◽  
Research Funding ◽  
Phase 1 ◽  
Phase 2 ◽  
Advisory Committees ◽  
Oncology Research ◽  
Equity Ownership ◽  
D 20 ◽  
Ecog Ps

Abstract Abstract 2940 Background: PD 0332991 is an orally bioavailable selective inhibitor of cyclin-dependent kinase (CDK) 4/6. Inhibition of CDK4/6 phosphorylation of retinoblastoma (Rb) induces prolonged early G1 cell cycle arrest (pG1) and synchronous progression to S phase (pG1-S) upon withdrawal, which sensitizes human multiple myeloma (MM) cells to killing by bortezomib (B) or dexamethasone (D) in vitro and in animal models. Based on these observations, a phase 1/2 study in combination with B plus D in patients (pts) with relapsed and/or refractory MM was initiated. The phase 1 part of the study (completed) determined the recommended phase 2 dose and schedule to be PD 0332991 100 mg QD 12 days on followed by 9 days off treatment in a 21-day cycle with intravenous B 1.0 mg/m2 plus oral D 20 mg administered on Days 8 and 11 in pG1 and 15 and 18 in pG1-S (Niesvizky et al. ASH 2010). We present preliminary data from the phase 2 part of the study. Methods: Pts with Rb protein-positive, measurable (as defined by International Myeloma Working Group [IMWG]) progressive, relapsed or refractory MM after ≥1 prior treatment were eligible. Prior B was allowed only if there was a response and disease progression occurred off therapy. Pts received oral PD 0332991 once daily on Days 1–12 in a 21-day cycle in combination with intravenous B 1.0 mg/m2 plus oral D 20 mg administered on Days 8, 11, 15, and 18. The primary endpoint is overall response rate (ORR); secondary endpoints include time to progression (TTP), progression-free survival (PFS), overall survival, duration of response, and safety. PD 0332991-mediated inhibition of CDK4/6-specific phosphorylation of Rb (pSRb) and Ki67 in bone marrow MM cells were also assessed. The phase 2 part of the study is a Simon Two-Stage Minimax design; 25 response evaluable patients were to be enrolled into the first stage. Results: 39 pts have been tested for Rb and 36 pts (92%) were positive. Of the 36 pts, 30 pts have been enrolled to date including 2 pts who did not receive the study treatment, and 23 pts are considered response evaluable as of the data cut-off. 56% of pts had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 1 and 8% had ECOG PS of 2. At baseline, median β2 microglobulin was 3.1 (range 1.6–26.2), median hemoglobin was 11.2 (7.2–13.6), median calcium was 9.4 (8.7–11.9). The median number of prior therapies was 2 (range 1–8); 55% had received prior B. Sixteen pts have discontinued (9 due to progressive disease, 3 due to AE, 2 consent withdrawal, and 2 not treated). The most common treatment-related AEs were thrombocytopenia (44%), nausea (20%), anemia, constipation, fatigue, and neutropenia (all 16%); 32% of pts reported grade ≥3 thrombocytopenia. IHC data showed on-treatment reduction in pSRb and Ki67 in MM cells from bone marrow of 3/3 patients with available samples. To date, 1 pt achieved a complete response (CR), 1 achieved a very good partial response (VGPR), 1 partial response (PR), 1 minor response (MR), and 5 stable disease (SD); 6 pts are too early for assessment. Conclusions: To date, the combination of PD 0332991 and B plus D has shown response in 4 pts with relapsed/refractory MM. The most commonly reported AEs were cytopenias, consistent with the known safety profiles of PD 0332991 and B. PD 0332991 inhibited phosphorylation of Rb and cell cycle progression in MM cells. The accrual to stage 1 is ongoing. Updated efficacy and safety data will be presented. Disclosures: Niesvizky: Millennium Pharmaceuticals: Consultancy; Millennium Pharmaceuticals: Research Funding; Millennium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Hess:Pfizer Oncology: Consultancy; Pfizer Oncology: Research Funding; Pfizer Oncology: Membership on an entity's Board of Directors or advisory committees. Spicka:Janssen-Cilag: Consultancy; Celgene: Consultancy; Celgene: Research Funding; Janssen-Cilag: Honoraria; Celgene: Honoraria; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Jakubczak:Pfizer Oncology: Employment; Pfizer Oncology: Equity Ownership. Kim:Pfizer Oncology: Equity Ownership; Pfizer Oncology: Employment. Randolph:Pfizer Oncology: Employment; Pfizer Oncology: Equity Ownership. Chen-Kiang:Pfizer Oncology: Research Funding.

Phase II Study of the Pan-Deacetylase Inhibitor Panobinostat in Combination with Bortezomib and Dexamethasone in Relapsed and Bortezomib-Refractory Multiple Myeloma (PANORAMA 2)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 814-814 ◽  
Author(s):  
Paul G. Richardson ◽  
Melissa Alsina ◽  
Donna M. Weber ◽  
Steven E. Coutre ◽  
Sagar Lonial ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Phase 1 ◽  
Treatment Phase ◽  
Employment Equity ◽  
Advisory Committees ◽  
Overall Response ◽  
Equity Ownership ◽  
Grade 3 ◽  
Stage 1

Abstract Abstract 814FN2 Background: Patients with refractory multiple myeloma (MM) have limited treatment options and an extremely poor prognosis. A recent study of patients who were refractory to bortezomib and were relapsed following, refractory to or ineligible to receive an immunomodulatory drug (IMiD, thalidomide or lenalidomide) demonstrated a median event-free survival of only 5 months (Kumar S et al, Leukemia, 2011). Panobinostat is an oral pan-deacetylase inhibitor (pan-DACi) that increases acetylation of proteins involved in multiple oncogenic pathways. Preclinical studies have demonstrated synergistic anti-myeloma activity of the combination of panobinostat and bortezomib through dual inhibition of the aggresome and proteasome pathways. In a phase I study (B2207) of patients with relapsed or relapsed/refractory MM treated with panobinostat + bortezomib, clinical responses (≥ minimal response [MR]) were observed in 65% of patients, including in patients with bortezomib-refractory disease. PANORAMA 2 seeks to expand upon these preliminary results and seeks to determine whether panobinostat can sensitize resistant patients to a bortezomib-containing therapeutic regimen. Methods: PANORAMA 2 is a single arm, phase II study of panobinostat + bortezomib + dexamethasone in patients with bortezomib-refractory MM. Patients with relapsed and bortezomib-refractory MM (≥ 2 prior lines of therapy including an IMiD and who had progressed on or within 60 days of the last bortezomib-based therapy) are treated in 2 phases. Treatment phase 1 consists of 8 three-week cycles of oral panobinostat (20 mg days 1, 3, 5, 8, 10, 12) + intravenous bortezomib (1.3 mg/m2 days 1, 4, 8, 11) + oral dexamethasone (20 mg on day of and after bortezomib). Patients demonstrating clinical benefit (≥ stable disease) can proceed to treatment phase 2, consisting of 4 six-week cycles of panobinostat (20 mg TIW 2 weeks on 1 week off, and repeat) + bortezomib (1.3 mg/m2 days 1, 8, 22, 29) + dexamethasone (20 mg on day of and after bortezomib). The primary endpoint is overall response (≥ partial response [PR]), as defined by the European Group of Blood and Marrow Transplantation 1998 criteria, in the first 8 cycles of treatment phase 1. A Simon 2-stage design is used to test the primary endpoint where ≥ 4 responses (≥ PR) in 24 patients are needed in stage 1 in order to proceed to stage 2, where ≥ 9 responses in all patients (N = 47) are required to reject the null hypothesis (overall response rate ≤ 10%). Results: A sufficient number of responses ≥ PR were observed in stage 1 to allow for enrollment to continue to stage 2. As of 15 July 2011, 53 patients with bortezomib-refractory MM were enrolled. Safety and demographic data were available for 48 patients. The median age was 61 (41–88) years. Patients were heavily pretreated, with a median of 4 (2–14) prior regimens, and most patients (69%) received prior autologous stem cell transplant. Efficacy data were available for 44 patients. At the time of this analysis, 9 patients achieved ≥ PR (2 near CR [nCR] and 7 PR) as best overall response, and an additional 7 patients achieved an MR. Responders exhibited a long duration on therapy, and, to date, 8 patients have proceeded to treatment phase 2. The 2 patients with nCR have received ≥ 10 cycles of treatment (duration of therapy 190 and 253 days). Four patients who achieved PR have received ≥ 9 cycles (duration of therapy 155–225 days). Updated response data will be presented. Common adverse events (AEs) of any grade included, fatigue (52%), diarrhea (41%), thrombocytopenia (38%), nausea (38%), and anemia (21%). Gastrointestinal AEs were generally mild, with a relatively low incidence of grade 3/4 events. Grade 3/4 AEs were generally hematologic in nature, with grade 3/4 thrombocytopenia, anemia, and neutropenia reported in 38%, 12%, and 10% of patients, respectively. Other common nonhematologic grade 3/4 AEs included fatigue (10%) and pneumonia (10%). Of note, to date, a relatively low rate of peripheral neuropathy (17%) has been observed. No grade 3/4 peripheral neuropathy has been observed. Conclusions: The combination of panobinostat and bortezomib is a promising treatment for patients with bortezomib-refractory MM. These data, along with forthcoming data from the phase III study of panobinostat/placebo + bortezomib + dexamethasone in patients with relapsed MM (PANORAMA 1), will further define the potential role of panobinostat in the treatment of patients with MM. Disclosures: Richardson: Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Alsina:Novartis: Research Funding; Celgene: Research Funding; Ortho Biotech: Research Funding; Onyx: Research Funding; Millennium: Consultancy, Research Funding. Weber:Millennium: Honoraria; Celgene: Honoraria, Research Funding; Novartis: Research Funding. Lonial:Millennium: Consultancy; Celgene: Consultancy; Merck: Consultancy; Onyx: Consultancy; BMS: Consultancy; Novartis: Consultancy. Gasparetto:Millennium: Speakers Bureau. Warsi:Novartis: Employment, Equity Ownership. Ondovik:Novartis: Employment, Equity Ownership. Mukhopadhyay:Novartis: Employment, Equity Ownership. Snodgrass:Novartis: Employment, Equity Ownership.

Subset Analysis of Response to Treatment of Chronic Phase CML in a Phase 1 Study of Ponatinib in Refractory Hematologic Malignancies

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 602-602 ◽  
Author(s):  
Jorge E. Cortes ◽  
Hagop M. Kantarjian ◽  
Neil Shah ◽  
Dale Bixby ◽  
Michael J. Mauro ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Median Time ◽  
Research Funding ◽  
Phase 1 ◽  
Chronic Phase ◽  
Hematologic Malignancies ◽  
Employment Equity ◽  
Advisory Committees ◽  
Mutation Status ◽  
Equity Ownership

Abstract Abstract 602 Background: Ponatinib is a potent, oral, pan-BCR-ABL inhibitor active against the native enzyme and all tested resistant mutants, including the uniformly resistant T315I mutation. Initial findings of a phase 1 trial in patients (pts) with refractory hematologic malignancies have been reported. The effect of duration of treatment, prior treatment, and mutation status on response to treatment was examined in CML chronic phase (CP) pts who responded to ponatinib. Methods: An open-label, dose escalation, phase 1 trial of ponatinib in pts with hematologic malignancies is ongoing. The primary aim is to assess the safety; anti-leukemic activity is also being investigated. Pts resistant to prior treatments or who had no standard treatment available were enrolled to receive a single daily oral dose of ponatinib (2 mg to 60 mg). Subset analyses of factors impacting cytogenetic and molecular response endpoints (MCyR and MMR) were performed for pts with CP-CML. Data are presented through April 15, 2011. Results: In total, 81 pts (54% male) received ponatinib. Overall, 43 pts had CP with 34 ongoing at analysis. MCyR was observed as best response in 31/43 (72%), 27 (63%) CCyR. The median time to MCyR was 12 (3 to 104) wks. Response rates were assessed by duration of treatment (1 pt in CCyR at entry was excluded; 6 pts in PCyR had to achieve CCyR). At the 3 month assessment, 22/42 (52%) CP pts achieved MCyR; at 6 months, 24/42 (57%); at 12 months, 29/42 (69%) had MCyR. The impact of prior treatment on response and time to response was assessed. 42 pts (98%) had >2 prior TKIs and 28 (65%) ≥3 prior TKIs, including investigational agents. Of approved TKIs, all pts were previously treated with imatinib, 19 dasatinib or nilotinib after imatinib, and 21 both dasatinib and nilotinib after imatinib. MCyR rate decreased with number of prior TKIs (2 prior TKIs 13/14 [93%], ≥3 prior TKIs 17/28 [61%]) and number of approved TKIs (imatinib followed by dasatinib or nilotinib 17/19 [90%], or by both dasatinib and nilotinib 12/21 [57%]). Time to response was prolonged in pts more heavily treated with prior TKIs. Median time to MCyR increased with the number of prior TKIs and approved TKIs (2 TKIs 12 wks, ≥3 TKIs 32 wks). The effect of mutation status on response and time to response was also evaluated. At entry, 12 pts had the T315I mutation, 15 had other BCR-ABL kinase domain mutations, 12 had no mutations detected, 4 did not allow sequencing. MCyR response rate for CP pts with T315I was 11/12 (92%); for other mutations, 10/15 (67%); and no mutation, 7/12 (58%). Similarly, mutation status had an impact on time to response: median time to MCyR was 12 wks for those with T315I or other mutations and 32 wks in resistant pts with no mutation. All CP patients were evaluable for MMR. At analysis, MMR was 17/43 (40%). MMR rate was inversely related to number of prior TKIs (2 TKIs 10/14 [71%], ≥3 TKIs 6/28 [21%]), approved TKIs (imatinib followed by dasatinib or nilotinib 12/19 [63%], or by both dasatinib and nilotinib 4/21 [19%]), and was higher for T315I pts (7/12, 58%) and those with other mutations (7/15, 47%) compared with no mutation (2/12, 17%). Median time to MMR for CP pts was 97 wks; median time to MMR was shorter for pts who were less heavily treated (2 prior TKIs 24 wks) and those with T315I or other mutations (63 wks). Conclusion: In this subset analysis of the phase 1 data, ponatinib had substantial activity in all subgroups analyzed. Time on treatment, less prior therapy and kinase domain mutations were associated with higher response rates and early responses in CP pts. Cytogenetic responses improved over the first 12 months of treatment and were higher in less heavily treated pts. Disclosures: Cortes: Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding. Kantarjian:Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; ARIAD: Research Funding. Shah:Ariad: Consultancy, Research Funding. Bixby:Novartis: Speakers Bureau; BMS: Speakers Bureau; GSK: Speakers Bureau. Mauro:ARIAD: Research Funding. Flinn:ARIAD: Research Funding. Hu:ARIAD: Employment. Clackson:ARIAD: Employment, Equity Ownership. Rivera:ARIAD: Employment, Equity Ownership. Turner:ARIAD: Employment, Equity Ownership. Haluska:ARIAD: Employment, Equity Ownership. Druker:MolecularMD: OHSU and Dr. Druker have a financial interest in MolecularMD. Technology used in this research has been licensed to MolecularMD. This potential conflict of interest has been reviewed and managed by the OHSU Conflict of Interest in Research Committee and t. Deininger:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Genzyme: Research Funding. Talpaz:ARIAD: Research Funding.

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