Phase 2 Multicenter Study of Tazemetostat, an EZH2 Inhibitor, in Patients with Relapsed or Refractory Follicular Lymphoma

Introduction: Relapsed/refractory (R/R) follicular lymphoma (FL) remains a difficult-to-treat condition, with limited treatment options. New, tolerable treatments with unique mechanisms of action are needed, especially for high-risk patients whose disease progresses within 24 months of diagnosis (POD24). The epigenetic regulator EZH2 catalyzes the histone 3 lysine 27 trimethylation (H3K27m3) gene suppressive mark, which is essential for BCL6-driven germinal center (GC) formation. Conversely, a reduction in EZH2 catalytic activity is required for centroblast differentiation and initiation of the GC exit program. Activating mutations (MT) in EZH2, present in ~20% of FL patients, and enhanced H3K27me3 prevent GC exit, resulting in GC hyperplasia and lymphomagenesis. Tazemetostat, an investigational, selective, oral EZH2 inhibitor, has demonstrated durable, single-agent, antitumor activity in R/R FL patients with MT or wild-type (WT) EZH2. Herein, we report newly emerging interim efficacy and safety data from the MT and WT cohorts and the POD24 subgroup. Methods: This open-label, multicenter, phase 2 study (NCT01897571) evaluated tazemetostat 800 mg administered orally twice daily in patients with MT or WT EZH2 R/R FL (Grade 1-3b). Key inclusion criteria included age ≥18 years, Eastern Cooperative Oncology Group performance status of 0-2, ≥2 prior treatment regimens, and measurable disease per 2007 IWG-NHL criteria. The primary endpoint was objective response rate (complete response + partial response). Secondary endpoints included progression-free survival and safety. The POD24 subgroup was composed of patients experiencing disease progression or relapse within 24 months of diagnosis or the start of frontline treatment with immunochemotherapy. Results: As of June 7, 2019, interim data were available for 99 patients (MT EZH2, n=45 [POD24, n=17; 38%]; WT EZH2, n=54 [POD24, n=30; 56%]). Of the 33 patients in the MT cohort with an objective response, 15 (45%) had a response at ≥6 months, 7 (21%) at ≥12 months, and 4 (12%) at ≥16 months. Of the 18 patients in the WT cohort with an objective response, 15 (83%) had a response at ≥6 months, 9 (50%) at ≥12 months, and 6 (33%) at ≥16 months. Data from the MT cohort continue to mature, with 11 (24%) patients enrolled in the past year and 17 (38%) patients still on treatment. Updated data from the fully enrolled MT cohort, and sub-group analyses from both WT and MT cohort, will be presented. Interim efficacy data from the response-evaluable population and POD24 subgroup of the MT and WT cohorts are presented in Table 1. These results demonstrate the potent, antitumor activity of tazemetostat regardless of the prognostic category of patients. Treatment-related Grade ≥3 adverse events (AEs) were reported in 17% of all patients and 15% of patients in the POD24 subgroup. The most frequently reported AEs were similar across the total population and the POD24 subgroup and included thrombocytopenia (3%), anemia (2%), asthenia (2%), vomiting (1%), and fatigue (1%). Five percent of all patients discontinued treatment, and 9% had dose reductions due to treatment-related AEs. No treatment-related Grade 5 AE and deaths were reported. Conclusion: Tazemetostat was generally well tolerated, with a low incidence of treatment-related AEs. Tazemetostat demonstrated clinically meaningful, durable, single-agent activity across a spectrum of patients with FL, including the POD24 subgroup, and pronounced responses in patients with EZH2 activating mutations. Disclosures Morschhauser: BMS: Honoraria; Roche/Genentech: Consultancy; Servier: Consultancy; Janssen: Honoraria; Celgene: Honoraria; Gilead: Consultancy. Tilly:servier: Honoraria; merck: Honoraria; roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Gilead: Honoraria; BMS: Honoraria; Karyopharm: Consultancy; Roche: Consultancy; Celgene: Consultancy, Research Funding; Astra-Zeneca: Consultancy. Phillips:Bayer: Consultancy; Incyte: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy; Seattle Genetics: Consultancy; Gilead: Consultancy; Abbvie: Research Funding; Pharmacyclics: Consultancy, Research Funding. Ribrag:Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Research Funding; ArgenX: Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees; AZ: Membership on an entity's Board of Directors or advisory committees; Nanostring: Membership on an entity's Board of Directors or advisory committees; Roche: Other: Travel, accommodations, and expenses ; BMS: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses . Campbell:Janssen: Honoraria, Research Funding, Speakers Bureau. Jurczak:Servier: Research Funding; Loxo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Research Funding; Takeda: Research Funding; Bayer: Research Funding; Celgene: Research Funding; Roche: Research Funding; Morphosys: Research Funding; TG Therapeutics: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celtrion: Research Funding; Sandoz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Gilead: Research Funding; AstraZeneca/Acerta: Membership on an entity's Board of Directors or advisory committees, Research Funding. McKay:Epizyme: Consultancy, Honoraria. Opat:Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Mundipharma: Consultancy, Honoraria. Radford:GSK: Equity Ownership; ADC Therapeutics: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; AstraZeneca: Equity Ownership, Research Funding; Novartis: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria. Whalen:Epizyme: Employment, Equity Ownership. Rajarethinam:Epizyme: Employment, Equity Ownership. Navia:Epizyme: Employment, Equity Ownership. Adib:Epizyme: Employment, Equity Ownership. Salles:Amgen: Honoraria, Other: Educational events; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Epizyme: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis, Servier, AbbVie, Karyopharm, Kite, MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Roche, Janssen, Gilead, Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events.

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Interim Results from an Ongoing Phase 2 Multicenter Study of Tazemetostat, an EZH2 Inhibitor, in Patients with Relapsed or Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL)

Blood ◽

10.1182/blood-2018-99-113411 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4196-4196 ◽

Cited By ~ 4

Author(s):

Vincent Ribrag ◽

Franck Morschhauser ◽

Pamela McKay ◽

Gilles Andre Salles ◽

Connie Lee Batlevi ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Single Agent ◽

B Cell Lymphoma ◽

Clinical Activity ◽

Phase 2 ◽

Employment Equity ◽

Advisory Committees ◽

Activating Mutations ◽

Equity Ownership

Abstract Background: R/R DLBCL remains an area of unmet medical need and treatments with novel mechanisms of action are urgently needed. Germinal center DLBCLs depend on the histone methyltransferase EZH2 to perpetuate a less-differentiated state and EZH2 activating mutations may be oncogenic drivers in a subset of patients (pts). Inhibition of EZH2 reprograms abnormal cell growth, leading to cell death or differentiation, and subsequent tumor regression. Tazemetostat, a potent, selective, oral EZH2 inhibitor has shown antitumor activity in a phase 1 study that included DLBCL pts with mutated (mt) or wild type (wt) EZH2 tumors, which provides rationale for further investigation of its single agent activity. This open-label, multicenter phase 2 study is evaluating tazemetostat in pts with either mt or wt EZH2 R/R DLBCL or follicular lymphoma (Grade 1-3b); results of an interim analysis of DLBCL pts treated with tazemetostat, as monotherapy or in combination with prednisolone are presented. Methods: Key inclusion criteria include: age ≥18 years, ≥2 prior treatment regimens, and measurable disease. Tazmetostat 800 mg is administered orally, twice daily (BID); prednisolone (40 mg/m2) on days 1 to 5 and days 15 to 19 in a 28-day cycle for 16 weeks. Response was assessed every 8 weeks using IWG-NHL assessment criteria (Cheson 2007). Tumor tissue was analyzed for EZH2 hot spot activating mutations (Y646X, A682G, A692V) using a cobas® EZH2 Mutation Test (Roche Molecular Systems; investigational use only). Hans algorithm was used to determine cell of origin. The primary endpoint is overall response rate (ORR). Secondary endpoints include progression-free survival (PFS), duration of response (DOR) and safety/tolerability. Results: As of May 1, 2018, interim phase 2 safety and activity data were summarized from 226 DLBCL pts (intent to treat analysis). Demographic and clinical activity information are provided in the table, including ORRs of 17% in both mt and wt arms and 9% in the prednisolone arm. Notably, DOR was substantially greater in the mt arm. Safety analysis showed that treatment-emergent adverse events (TEAE) leading to study drug discontinuation or withdrawal from study occurred in 12% of pts. Grade ≥3 treatment-related AEs were reported in 27% of pts. The most common (≥10%) TEAEs (all grades) were: thrombocytopenia (20%), nausea (17%), anemia (15%), neutropenia (15%), vomiting (15%), cough (14%), diarrhea (12%), fatigue (12%), pyrexia (12%), abdominal pain (11%) and asthenia (10%). Conclusion: Tazemetostat was generally well tolerated at a dose of 800 mg BID, as monotherapy or in combination with prednisolone. In this difficult to treat, heavily pretreated, refractory patient population, clinical activity was observed in approximately 20% of monotherapy pts, regardless of mutational status, many of whom had received multiple prior lines of therapy. Tazemetostat in combination with prednisolone did not result in improved activity compared with tazemetostat monotherapy. Disclosures Ribrag: Servier, Pharmamar, Nanostring, Gilead, Infinity, BMS, MSD, Epizyme: Consultancy; Roche: Other: Travel, expenses, accommodation; ESAI: Honoraria, Research Funding. Morschhauser:Epizyme: Consultancy; Roche/Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, 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; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees. McKay:Epizyme: Consultancy, Honoraria. Salles:Roche, Jannsen, Gilead, Celgene, Novartis, Amgen, BMS, Merck, Servier: Honoraria. Tilly:Roche: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Cartron:Sanofi: Honoraria; Roche: Consultancy, Honoraria; Gilead Sciences: Honoraria; Janssen: Honoraria; Celgene: Consultancy, Honoraria. Gribben:Unum: Equity Ownership; Novartis: Honoraria; TG Therapeutics: Honoraria; Abbvie: Honoraria; Medical Research Council: Research Funding; Janssen: Honoraria, Research Funding; Roche: Honoraria; NIH: Research Funding; Wellcome Trust: Research Funding; Cancer Research UK: Research Funding; Pharmacyclics: Honoraria; Kite: Honoraria; Acerta Pharma: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Dickinson:GSK: Consultancy. Opat:Roche, Celgene, Mundipharma, Janssen: Honoraria; Roche, Celgene, Mundipharma, Janssen: Consultancy. Adib:Epizyme: Employment, Equity Ownership. Blakemore:Epizyme: Employment, Equity Ownership. Larus:Epizyme: Employment, Equity Ownership. Johnson:Zenyaku Kogyo: Other: Travel, accommodations, expenses; Eisai: Research Funding; Incyte: Consultancy; Genmab: Consultancy; Kite: Consultancy; Boeringher Ingelheim: Consultancy; Epizyme: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Research Funding; Celgene: Honoraria; Novartis: Honoraria; Takeda: Honoraria, Travel, accommodations, expenses; Bristol-Myers Squibb: Honoraria.

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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 ◽

10.1182/blood.v124.21.396.396 ◽

2014 ◽

Vol 124 (21) ◽

pp. 396-396 ◽

Cited By ~ 17

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.

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Ublituximab (TG-1101), a Novel Glycoengineered Anti-CD20 Monoclonal Antibody, in Combination with Ibrutinib Is Highly Active in Patients with Relapsed and/or Refractory CLL and MCL; Results of a Phase II Trial

Blood ◽

10.1182/blood.v124.21.4679.4679 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4679-4679 ◽

Cited By ~ 5

Author(s):

Jeff P. Sharman ◽

Charles M. Farber ◽

Daruka Mahadevan ◽

Marshall T. Schreeder ◽

Heather D. Brooks ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Alkylating Agent ◽

Single Agent ◽

Employment Equity ◽

Advisory Committees ◽

Highly Active ◽

Efficacy Assessment ◽

Equity Ownership ◽

Anti Cd20

Abstract Introduction: Ublituximab (UTX) is a novel, chimeric monoclonal antibody (mAb) which targets a unique epitope on the CD20 antigen and has been glycoengineered to enhance affinity for all variants of FcγRIIIa receptors, demonstrating greater antibody-dependent cellular cytotoxicity (ADCC) activity than rituximab and ofatumumab, particularly against cells that express low CD20 levels. Two Phase I trials of single agent UTX in relapsed/refractory CLL reported significant response rates with rapid and sustained lymphocyte depletion and a manageable safety profile. Ibrutinib, a novel oral BTK inhibitor approved for patients with previously treated CLL and MCL, displays high single agent activity and has reported increased activity in combination with non-glycoengineered anti-CD20 mAbs. Herein we report safety and efficacy data on the first combination of ibrutinib with a glycoengineered anti-CD20 mAb, UTX, from an ongoing Phase 2 trial. Methods: Eligible patients have relapsed or refractory CLL/SLL or MCL with an ECOG PS ≤ 2. The study was designed to assess safety, tolerability, and early overall response rate, with an initial safety run-in period consisting of 6 patients followed by open enrollment. UTX (Cohorts of 600 and 900 mg for CLL and at 900 mg for MCL patients) is administered on Days 1, 8, and 15 in Cycle 1 followed by Day 1 of Cycles 2 - 6. Ibrutinib is started on Day 1 and continues daily at 420 mg and 560 mg for CLL and MCL patients respectively. Following Cycle 6, patients come off study but remain on ibrutinib. Primary endpoint for safety: Adverse Events and Dose Limiting Toxicities (DLT) during safety run-in. Phase II primary efficacy endpoint: ORR with an emphasis on early activity with response assessments by CT scan scheduled prior to cycles 3 and 6 only. Results: 40 patients (33 CLL/ 7 MCL) have been enrolled to date with enrollment continuing. 23 M/17 F, median age 72 yr (range 52-86), ECOG 0/1/2: 20/19/1, median prior Tx = 2 (range 1-6), 38% with ≥ 2 prior anti-CD20 therapies; prior purine analog = 43%; prior alkylating agent = 68%; and prior purine and alkylating agent = 43%. No DLTs were observed during the safety run-in. Gr 3/4 AE’s occurring in at least 5% of patients and at least possibly related to UTX and/or ibrutinib included: neutropenia, thrombocytopenia, diarrhea, rash, leukocytosis, and infusion related reaction. There were no Grade 3/4 adverse events reported in ≥ 10% of patients. Ibrutinib was dose reduced due to an AE in 2 patients (1 diarrhea, 1 rash) and discontinued in 2 patients due to ibrutinib related AE’s (diarrhea and rash). IRR’s were managed with infusion interruptions with no patient requiring an ublituximab dose reduction. As of July 2014, 24/40 patients are evaluable for response. Best response to treatment is as follows: TableTypePts (n)CR (n)PR (n)SD (n)ORR (%)CLL non 17p/11q10-9190%17p/11q817-100%Total CLL18116194%MCL632183% The one CLL patient who achieved stable disease had a 46% nodal reduction. UTX appears to control ibrutinib related lymphocytosis with more than half of the patients within normal range for ALC by first efficacy assessment. Conclusions: Data suggests ublituximab, a glycoengineered anti-CD20 mAb, in combination with ibrutinib is both well-tolerated and highly active in patients with relapsed or refractory CLL and MCL. ORR was 94% in patients with CLL (100% in patients with high risk CLL: 17p, 11q del with 1 CR), with responses attained rapidly (median TTR: 8 weeks). In MCL, 83% of patients achieved a response at first efficacy assessment, with 50% of patients achieving a CR by week 20. For most patients, responses improved by the second efficacy assessment. The addition of ublituximab appears to mitigate ibrutinib related lymphocytosis producing earlier clinical responses than historically seen with ibrutinib monotherapy. Efficacy and safety will be updated on all enrolled patients. Disclosures Sharman: TG Therapeutics: Research Funding; Gilead: Consultancy, Research Funding; Roche: Research Funding; Pharmacyclics: Research Funding; Celgene: Consultancy, Research Funding. Farber:Leukemia Lymphoma Society NJ Chapter: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Alexion: Stock ownership Other. Schreeder:TG Therapeutics, Inc.: Research Funding. Kolibaba:TG Therapeutics: Research Funding; Gilead: Research Funding; Glaxo Smithkline: Research Funding. Sportelli:TG Therapeutics: Employment, Equity Ownership. Miskin:TG Therapeutics, Inc.: Employment, Equity Ownership. Weiss:TG Therapeutics, Inc.: Employment, Equity Ownership. Greenwald:TG Therapeutics: Research Funding.

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Targeted MEK Inhibition in Patients with Previously Treated Multiple Myeloma

Blood ◽

10.1182/blood.v124.21.4775.4775 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4775-4775 ◽

Cited By ~ 4

Author(s):

Christoph Heuck ◽

Yogesh Jethava ◽

Rashid Z Khan ◽

Scott Miller ◽

Alan Mitchell ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Mapk Pathway ◽

Objective Response ◽

Genomic Profiling ◽

Employment Equity ◽

Advisory Committees ◽

Comprehensive Genomic Profiling ◽

Equity Ownership

Abstract Background: Diagnostic and therapeutic advances have significantly improved the outcomes for multiple myeloma (MM) patients. However, pts who are refractory to or relapse after therapy with immune modulatory drugs and proteasome inhibitors remain a therapeutic challenge. Comprehensive genomic profiling via clinical next generation sequencing (NGS)-based assays studies of MM cases have revealed multiple targetable mutations that were previously unexploited in MM. Methods: Between June 2013 and May 2014 we performed genomic profiling of 351 patients who had progressed after initial therapy to assist physicians in therapy planning. Comprehensive genomic profiling was performed using the FoundationOne¨ or FoundationOne Heme¨ assays. FoundationOne assays 374 cancer-related and 24 frequently rearranged genes via DNA-seq, and FoundationOneHeme assays 405 cancer-related and 31 frequently rearranged genes via DNA-seq as well as 265 frequently rearranged genes by RNA-seq. All samples were sequenced in a CLIA-certified CAP-accredited laboratory to an average depth >500x . Patients with activating alterations of KRAS, NRAS or BRAF were considered for therapy with the targeted agent trametinib (TMTB) as were patients who had a gene expression signature suggesting activation of the MAPK pathway. Retrospective review of this case series was approved by the UAMS institutional review board. Results: We identified 63 patients who underwent treatment with Trametinib. 60 were treated based on activating mutations of KRAS, NRAS or BRAF and 3 were treated based on a GEP signature. The median age was 65 and patients had a median of 5 lines of prior therapy (range 1-20). 38 of 63 patients had prior treatment with Total Therapy. 43 underwent salvage with chemotherapy prior to initiation of TMTB, 15 had salvage transplants, 33 patients were exposed to novel agents (Pomalidomide, Carfilzomib) and 33 had Metronomic therapy before TMTB. 25% of patients were ISS stage 3 and 37% had GEP70 defined high risk. 13 had PET defined extra medullary disease (EMD). 41 patients were administered TMTB monotherapy and 22 received TMTB treatment in combination with other agents. In general the treatment was well tolerated. 10 patients discontinued therapy because of toxicities, 29 discontinued because of disease progression or death. None of the deaths were attributed to TMTB, Best treatment responses were SD in 30, PR in 8, VGPR in 2 and CR in 3 of the 63 pts. For 25 patients with evaluable PET data, treatment resulted in complete resolution of FDG avid lesions in 9 patients and a better than 50% reduction in 15 (Figure 1). We will present updated data on clinical responses as well as toxicities. Conclusions: Treatment with targeted therapy guided by prospective comprehensive genomic profiling across all classes of genomic alterations in this heavily pretreated population of MM patients resulted in an unexpectedly high objective response rate. Observation of CR with TMTB monotherapy further supports continued investigation of this individualized approach to MM management. Disclosures Van Laar: Signal Genetics: Employment, Equity Ownership. Ali:Foundation Medicine, Inc.: Employment, Equity Ownership. Miller:Foundation Medicine, Inc: Employment. Zangari:Norvartis: Membership on an entity's Board of Directors or advisory committees; Onyx: Research Funding; Millennium: Research Funding. van Rhee:Millenium: Speakers Bureau; Sanofi: Speakers Bureau; Celgene: Speakers Bureau; Janssen: Speakers Bureau. Morgan:Celgene Corp: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Myeloma UK: Membership on an entity's Board of Directors or advisory committees; International Myeloma Foundation: Membership on an entity's Board of Directors or advisory committees; The Binding Site: Membership on an entity's Board of Directors or advisory committees; MMRF: Membership on an entity's Board of Directors or advisory committees.

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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 ◽

10.1182/blood.v128.22.4509.4509 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4509-4509 ◽

Cited By ~ 4

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.

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Interim Results from Fight-203, a Phase 2, Open-Label, Multicenter Study Evaluating the Efficacy and Safety of Pemigatinib (INCB054828) in Patients with Myeloid/Lymphoid Neoplasms with Rearrangement of Fibroblast Growth Factor Receptor 1 (FGFR1)

Blood ◽

10.1182/blood-2018-99-110388 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 690-690 ◽

Cited By ~ 12

Author(s):

Srdan Verstovsek ◽

Alessandro M. Vannucchi ◽

Alessandro Rambaldi ◽

Jason R. Gotlib ◽

Adam J. Mead ◽

...

Keyword(s):

Bone Marrow ◽

Board Of Directors ◽

Research Funding ◽

Phosphate Binders ◽

Phase 2 ◽

Open Label ◽

Employment Equity ◽

Advisory Committees ◽

Lymphoid Neoplasms ◽

Equity Ownership

Abstract Introduction: Myeloid/lymphoid neoplasms (MLNs) with rearrangement of FGFR1 on chromosome band 8p11 are rare but aggressive neoplasms characterized by heterogeneous presentation with myeloid and/or lymphoid proliferation, extramedullary involvement, and rapid progression to blast phase (Strati P, et al., Leuk Lymphoma. 2018;59:1672-1676). FGFR1 gets constitutively activated through fusion genes involving various partner genes, most frequently ZMYM2-FGFR1 or BCR-FGFR1 as consequence of a t(8;13)(p11;q12) or a t(8;22)(p11;q11), respectively. Chemotherapy is usually ineffective, effective targeted treatment has not been described, and allogeneic hematopoietic stem cell transplant (alloHSCT) is the only potentially curative option. Pemigatinib, a selective, potent, oral inhibitor of FGFR1, 2, and 3, has shown efficacy in patients with FGF/FGFR-activated tumors, including cholangiocarcinoma and urothelial carcinoma. We report interim results from the ongoing fight-203 study (NCT03011372) of pemigatinib in patients with FGFR1-rearranged MLNs. Methods: Fight-203 is a phase 2, open-label study enrolling patients ≥ 18 years of age with FGFR1-rearranged MLN. Patients enrolled in the study must have progressed on ≥ 1 prior treatment and be ineligible for alloHSCT. Patients receive a daily oral dose of pemigatinib 13.5 mg on a 21-day cycle (2 weeks on, 1 week off) until disease progression or unacceptable toxicity. The primary endpoint is overall clinical benefit rate, which includes complete clinical (CR) or partial clinical response (PR), and either complete or partial cytogenetic response (CCyR, PCyR). Secondary endpoints include duration of response/benefit, progression-free survival, overall survival, and safety/tolerability. Efficacy is assessed by evaluation of bone marrow histomorphology changes, standard cytogenetic and FISH evaluation of the FGFR1 rearrangement, and PET/CT scan. Results: At data cutoff (July 23, 2018), 14 patients were enrolled. Ten patients who had ≥ 1 response assessment were included in the analysis (Table). Patients received an average of 6.9 cycles of pemigatinib (range, 2-12 cycles). Median number of prior lines of therapy was 3 (range, 0-5), including 2 patients who received alloHSCT. Eight patients (80%) had a major CyR, including 6 patients with CCyR and 2 with PCyR. Eight patients (80%) had a CR or PR in bone marrow, peripheral blood, and extramedullary disease. One patient died of progression to myeloid blast crisis, 2 patients were bridged to alloHSCT, and 7 patients are ongoing. The most common treatment-emergent adverse events (AEs) were hyperphosphatemia (n=7 [70%]), diarrhea (n=5 [50%]) and anemia (n=5 [50%]); hyperphosphatemia was managed with diet and phosphate binders. Nine events in 4 patients (40%) were grade 3/4; 2 of these events (diarrhea and leukopenia) in 2 patients were related to pemigatinib. There were no drug-related AEs leading to dose interruption, dose reduction, or discontinuation. Conclusions: Pemigatinib showed promising efficacy, with an 80% major CyR rate accompanied by complete or partial remission, and was generally well tolerated by patients with FGFR1-rearranged MLN. The protocol was amended to allow continuous dosing, and the study is currently enrolling. Disclosures Verstovsek: Celgene: Membership on an entity's Board of Directors or advisory committees; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Gotlib:Blueprint Medicines: Consultancy, Honoraria, Research Funding; Deciphera: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Research Funding; Promedior: Research Funding; Kartos: Consultancy; Incyte: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Mead:Celgene: Research Funding; Bristol-Myers Squibb: Consultancy; Evotek: Research Funding; ARIAD: Consultancy; Cell Therapeutics: Consultancy; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Elstar: Research Funding. Hochhaus:Bristol-Myers Squibb: Research Funding; Novartis: Research Funding; Incyte: Research Funding; Takeda: Research Funding; Pfizer: Research Funding. Kiladjian:AOP Orphan: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: 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. Hernandez Boluda:Incyte: Consultancy; Novartis: Consultancy. Asatiani:Incyte: Employment, Equity Ownership. Lihou:Incyte: Employment, Equity Ownership. Zhen:Incyte: Employment, Equity Ownership. Reiter:Incyte: Consultancy, Honoraria.

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Imerge: A Study to Evaluate Imetelstat (GRN163L) in Transfusion-Dependent Subjects with IPSS Low or Intermediate-1 Risk Myelodysplastic Syndromes (MDS) That Is Relapsed/Refractory to Erythropoiesis-Stimulating Agent (ESA) Treatment

Blood ◽

10.1182/blood-2019-127435 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4248-4248 ◽

Cited By ~ 1

Author(s):

Uwe Platzbecker ◽

David P. Steensma ◽

Koen Van Eygen ◽

Azra Raza ◽

Valeria Santini ◽

...

Keyword(s):

Board Of Directors ◽

Myelodysplastic Syndromes ◽

Research Funding ◽

Phase 2 ◽

Employment Equity ◽

Phase 3 ◽

Advisory Committees ◽

Equity Ownership ◽

The Impact ◽

Rbc Transfusion

Background: Current treatment options for red blood cell (RBC) transfusion-dependent (TD) patients with lower risk (LR) myelodysplastic syndromes (MDS) relapsed after or refractory to erythropoiesis-stimulating agents (ESAs) have limited efficacy and durability; new approaches are needed. Imetelstat is a 13-mer lipid-conjugated oligonucleotide that targets the RNA template of human telomerase and is a competitive inhibitor of telomerase enzymatic activity (Asai et al, Cancer Res 2003; Herbert et al, Oncogene 2005). Preclinical, in vivo xenograft models (Dikmen et al, Cancer Res 2005; Hochreiter et al, Clin Cancer Res 2006) and preliminary clinical data from a pilot study conducted at Mayo Clinic (Tefferi et al, Blood Cancer Journal 2016) supported initiation of a study in TD LR MDS patients. A Phase 2 study of imetelstat, IMerge, demonstrated an 8-week RBC transfusion independence (RBC-TI) rate of 42%, 24-week RBC-TI rate of 29%, and 68% erythroid hematologic improvement (HI-E) rate in 38 heavily TD patients (median prior RBC transfusion burden 8 units / 8 weeks over the 16 weeks pre-study period) with LR MDS. Responses were durable with median duration of 8-week RBC-TI of 85.9 weeks by Kaplan Meier estimates (range 8.0-140.9) (Steensma ASH 2018, Fenaux EHA 2019). These Phase 2 results provided further evidence of potential clinical benefit of imetelstat treatment in TD LR MDS, and supported initiation of a Phase 3 trial. Methods: IMerge is two-part, Phase 2/3 study (ClinicalTrials.gov: NCT02598661). The Phase 2 portion of the study described above is closed for enrollment. The Phase 3 portion of the study is open for enrollment of adult patients with International Prognostic Scoring System (IPSS) low or intermediate-1 risk, non-del(5q) MDS, who are TD, are relapsed after or refractory to ESAs, and have not received treatment with lenalidomide or hypomethylating agents. The study is a randomized (2:1) double-blind, placebo-controlled trial to compare efficacy of imetelstat vs. placebo that will enroll approximately 170 patients and will be conducted at approximately 90 centers in North America, Europe, Asia and Middle East. Imetelstat will be administered as 2-hour IV infusion every 4 weeks at 7.5 mg/kg. The primary endpoint of the study is to assess the rate of RBC-TI lasting ≥8 weeks. Secondary endpoints include safety, rate of RBC-TI ≥24 weeks, time to RBC-TI start, RBC-TI duration, rate of HI-E, the amount and relative change in RBC transfusions, rate of CR or PR, overall survival, progression of MDS, pharmacokinetics and effect of treatment on quality of life. Biomarkers relevant to the mechanism of action of imetelstat will be assessed to demonstrate target inhibition and their association with clinical responses. Cytogenetics and mutation analyses will be performed to evaluate the impact of imetelstat on reduction/depletion of malignant clones leading to disease modification. Disclosures Platzbecker: Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria. Steensma:Astex: Consultancy; Arrowhead: Equity Ownership; Summer Road: Consultancy; Onconova: Consultancy; Aprea: Research Funding; Pfizer: Consultancy; Stemline: Consultancy; H3 Biosciences: Other: Research funding to institution, not investigator.. Santini:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Honoraria; Acceleron: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Menarini: Membership on an entity's Board of Directors or advisory committees. Germing:Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria; Amgen: Honoraria. Font:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees. Díez-Campelo:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Patnaik:Stem Line Pharmaceuticals.: Membership on an entity's Board of Directors or advisory committees. Sherman:Geron Corporation: Employment, Equity Ownership. Dougherty:Geron Corporation: Employment, Equity Ownership. Feller:Geron Corporation: Employment. Sun:Geron Corporation: Employment, Equity Ownership. Wan:Geron Corporation: Employment, Equity Ownership. Huang:Geron Corporation: Employment, Equity Ownership. Rizo:Geron Corporation: Employment, Equity Ownership. Fenaux:Celgene Corporation: Honoraria, Research Funding; Aprea: Research Funding; Astex: Honoraria, Research Funding; Jazz: Honoraria, Research Funding.

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Phase 2 Study of the Response and Safety of P-Bcma-101 CAR-T Cells in Patients with Relapsed/Refractory (r/r) Multiple Myeloma (MM) (PRIME)

Blood ◽

10.1182/blood-2019-129562 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3184-3184 ◽

Cited By ~ 16

Author(s):

Caitlin L. Costello ◽

Tara K. Gregory ◽

Syed Abbas Ali ◽

Jesus G. Berdeja ◽

Krina K. Patel ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Board Of Directors ◽

Research Funding ◽

Phase 2 ◽

Employment Equity ◽

Advisory Committees ◽

Car T Cells ◽

Car T ◽

Equity Ownership

P-BCMA-101 is a novel chimeric antigen receptor (CAR)-T cell product targeting B Cell Maturation Antigen (BCMA). P-BCMA-101 is produced using the piggyBac® (PB) DNA Modification System instead of the viral vector that is used with most CAR-T cells, requiring only plasmid DNA and mRNA. This makes it less costly and produces cells with a high percentage of the favorable T stem cell memory phenotype (TSCM). The higher cargo capacity of PB permits the incorporation of multiple genes in addition to CAR(s), including a safety switch allowing for rapid CAR-T cell elimination with a small molecule drug infusion in patients if desired, and a selection gene allowing for enrichment of CAR+ cells. Rather than using a traditional antibody-based binder, P-BCMA-101 has a Centyrin™ fused to a CD3ζ/4-1BB signaling domain. Centyrins are fully human proteins with high specificity and a large range of binding affinities, but are smaller, more stable and potentially less immunogenic than traditional scFv. Cumulatively, these features are predicted to result in a greater therapeutic index. A Phase 1, 3+3 dose escalation from 0.75 to 15 x 106 P-BCMA-101 CAR-T cells/kg (RP2D 6-15 x 106 cells/kg) was conducted in patients with r/r MM (Blood 2018 132:1012) demonstrating excellent efficacy and safety of P-BCMA-101, including notably low rates and grades of CRS and neurotoxicity (maximum Grade 2 without necessitating ICU admission, safety switch activation or other aggressive measures). These results supported FDA RMAT designation and initiation of a pivotal Phase 2 study. A Phase 2 pivotal portion of this study has recently been designed and initiated (PRIME; NCT03288493) in r/r MM patients who have received at least 3 prior lines of therapy. Their therapy must have contained a proteasome inhibitor, an IMiD, and CD38 targeted therapy with at least 2 of the prior lines in the form of triplet combinations. They must also have undergone ≥2 cycles of each line unless PD was the best response, refractory to the most recent line of therapy, and undergone autologous stem cell transplant or not be a candidate. Patients are required to be >=18 years old, have measurable disease by International Myeloma Working Group criteria (IMWG; Kumar 2016), adequate vital organ function and lack significant autoimmune, CNS and infectious diseases. No pre-specified level of BCMA expression is required, as this has not been demonstrated to correlate with clinical outcomes for P-BCMA-101 and other BCMA-targeted CAR-T products. Interestingly, unlike most CAR-T products patients may receive P-BCMA-101 after prior CAR-T cells or BCMA targeted agents, and may be multiply infused with P-BCMA-101. Patients are apheresed to harvest T cells, P-BCMA-101 is then manufactured and administered to patients as a single intravenous (IV) dose (6-15 x 106 P-BCMA-101 CAR-T cells/kg) after a standard 3-day cyclophosphamide (300 mg/m2/day) / fludarabine (30 mg/m2/day) conditioning regimen. One hundred patients are planned to be treated with P-BCMA-101. Uniquely, given the safety profile demonstrated during Phase 1, no hospital admission is required and patients may be administered P-BCMA-101 in an outpatient setting. The primary endpoints are safety and response rate by IMWG criteria. With a 100-subject sample, the Phase 2 part of the trial will have 90% power to detect a 15-percentage point improvement over a 30% response rate (based on that of the recently approved anti-CD38 antibody daratumumab), using an exact test for a binomial proportion with a 1-sided 0.05 significance level. Multiple biomarkers are being assessed including BCMA and cytokine levels, CAR-T cell kinetics, immunogenicity, T cell receptor diversity, CAR-T cell and patient gene expression (e.g. Nanostring) and others. Overall, the PRIME study is the first pivotal study of the unique P-BCMA-101 CAR-T product, and utilizes a number of novel design features. Studies are being initiated in combination with approved therapeutics and earlier lines of therapy with the intent of conducting Phase 3 trials. Funding by Poseida Therapeutics and the California Institute for Regenerative Medicine (CIRM). Disclosures Costello: Takeda: Honoraria, Research Funding; Janssen: Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Gregory:Poseida: Research Funding; Celgene: Speakers Bureau; Takeda: Speakers Bureau; Amgen: Speakers Bureau. Ali:Celgene: Research Funding; Poseida: Research Funding. Berdeja:Amgen Inc, BioClinica, Celgene Corporation, CRISPR Therapeutics, Bristol-Myers Squibb Company, Janssen Biotech Inc, Karyopharm Therapeutics, Kite Pharma Inc, Prothena, Servier, Takeda Oncology: Consultancy; AbbVie Inc, Amgen Inc, Acetylon Pharmaceuticals Inc, Bluebird Bio, Bristol-Myers Squibb Company, Celgene Corporation, Constellation Pharma, Curis Inc, Genentech, Glenmark Pharmaceuticals, Janssen Biotech Inc, Kesios Therapeutics, Lilly, Novartis, Poseida: Research Funding; Poseida: Research Funding. Patel:Oncopeptides, Nektar, Precision Biosciences, BMS: Consultancy; Takeda, Celgene, Janssen: Consultancy, Research Funding; Poseida Therapeutics, Cellectis, Abbvie: Research Funding. Shah:University of California, San Francisco: Employment; Genentech, Seattle Genetics, Oncopeptides, Karoypharm, Surface Oncology, Precision biosciences GSK, Nektar, Amgen, Indapta Therapeutics, Sanofi: Membership on an entity's Board of Directors or advisory committees; Indapta Therapeutics: Equity Ownership; Celgene, Janssen, Bluebird Bio, Sutro Biopharma: Research Funding; Poseida: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Nkarta: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees; Teneobio: Consultancy, Membership on an entity's Board of Directors or advisory committees. Ostertag:Poseida Therapeutics, Inc.: Employment, Equity Ownership. Martin:Poseida Therapeutics, Inc.: Employment, Equity Ownership. Ghoddusi:Poseida Therapeutics, Inc.: Employment, Equity Ownership. Shedlock:Poseida Therapeutics, Inc.: Employment, Equity Ownership. Spear:Poseida Therapeutics, Inc.: Employment, Equity Ownership. Orlowski:Poseida Therapeutics, Inc.: Research Funding. Cohen:Poseida Therapeutics, Inc.: Research Funding.

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Systemic Exposure of Rituximab Increased By Ibrutinib: Pharmacokinetic Results from the Helios Trial

Blood ◽

10.1182/blood.v128.22.4403.4403 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4403-4403

Author(s):

Paula Cramer ◽

Fatih Demirkan ◽

Graeme Fraser ◽

Alexander Pristupa ◽

Nancy L Bartlett ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Single Agent ◽

Systemic Exposure ◽

Tumor Burden ◽

Time Data ◽

Employment Equity ◽

Advisory Committees ◽

Concentration Time ◽

Equity Ownership

Abstract Background: Ibrutinib, an inhibitor of Bruton's tyrosine kinase, is indicated for the treatment of several B-cell malignancies. In the phase 3 HELIOS trial, the addition of ibrutinib to a bendamustine plus rituximab regimen significantly improved patient outcomes, including quality of life, overall response, and progression-free survival, in patients with relapsed/refractory chronic lymphocytic leukemia (CLL; Chanan-Khan, Lancet Oncol 2016; 17:200-211). Here we report the results from analyses exploring the pharmacokinetic (PK) interactions between ibrutinib, bendamustine, and rituximab from the HELIOS trial. Methods: In total, 578 patients were randomized to 420 mg ibrutinib (n = 289) or placebo (n = 289) in combination with 6 cycles of bendamustine and rituximab until disease progression or unacceptable toxicity. The bendamustine intravenous (IV) dose was 70 mg/m2 on days 2-3 of cycle 1 and days 1-2 of cycles 2-6; the rituximab IV dose was 375 mg/m2 on day 1 of cycle 1 and 500 mg/m2 in cycles 2-6. Infusion durations were typically 30 min for bendamustine and varied based on tolerability and infusion rates for rituximab. Ibrutinib PK samples were collected from all patients at predose, 1, 2, and 4 hr on day 1 of cycles 1 and 2. In a subset of patients, bendamustine PK samples were collected on day 2 of cycles 1 and 2 at predose, end of infusion, and at 1, 2, and 4 hr. Rituximab PK samples were collected on days 1 (predose) and 15 of cycle 1, day 1 (predose) of cycles 2-6, and on day 1 of cycles 7-9. Dose-normalized bendamustine and rituximab concentration-time data were stratified by treatment to evaluate the effect of ibrutinib on the PK of these drugs. Descriptive statistics were calculated using R (www.R-project.org). Results:PK samples from 178 patients were analyzed; 84 patients from the placebo arm and 94 patients from the ibrutinib arm. The mean dose ± standard deviation (SD) of bendamustine was 68.2 ± 6.3 mg/m2 and 68.9 ± 4.7 mg/m2 in patients receiving ibrutinib and placebo, respectively; the doses of rituximab were 468.1 ± 55.3 mg/m2 and 465.2 ± 65.0 mg/m2, respectively. The dose-normalized plasma concentration-time data of bendamustine (a cytochrome P450 1A2 substrate) from both arms were comparable, indicating that ibrutinib did not alter bendamustine PK. In contrast, systemic exposure of rituximab was higher in patients coadministered with ibrutinib than in patients who received placebo; mean predose serum concentrations were 2- to 3-fold higher in the first three cycles and 1.2- to 1.7-fold higher in subsequent cycles (Figure). The systemic exposure of ibrutinib (n = 280; mean area under the plasma drug concentration-time curve at steady state ± SD = 447.5 ± 298.2 ng•h/mL) in patients receiving the 420 mg dose was comparable to exposures observed in studies of single agent ibrutinib (Marostica, Cancer Chemother Pharmacol 2015; 75:111-121), indicating that bendamustine and rituximab did not impact the PK of ibrutinib. No relevant differences in safety profile were observed between the ibrutinib and placebo arm with the increase in systemic exposure of rituximab. All-grade infusion-related reactions were more frequent with placebo than with ibrutinib (22% vs. 16.7%, respectively), and the incidence of chills was comparable (~11%). Dose interruptions, dose reductions, and discontinuations due to infusion-related reaction were more frequent in the placebo arm (34.8% vs. 27.9%). Additional analyses to model the rituximab PK data using metrics of tumor burden as covariates (e.g., sum of the products of diameters) are currently ongoing and will be presented. Conclusions:Coadministration of ibrutinib with bendamustine and rituximab did not affect the PK of bendamustine or ibrutinib but led to greater dose-normalized systemic exposure of rituximab when compared to patients who received placebo. Rituximab has been reported to be characterized by target-mediated drug disposition (TMDD; Li, J Clin Pharmacol 2012; 52:1918-1926), which may describe many rituximab PK features, such as PK differences in CLL, non-Hodgkin's lymphoma, and rheumatoid arthritis and the dependency of PK behavior on baseline tumor burden. TMDD may account for the rituximab PK findings from this study, with the early decreased tumor burden following ibrutinib resulting in decreased rituximab clearance and hence higher systemic exposure. The clinical significance of this finding needs additional exploration. Disclosures Cramer: Mundipharma: Other: Travel, Accommodations, Expenses; Janssen-Cilag: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Astellas: Other: Travel, Accommodations, Expenses; Novartis: Consultancy, Research Funding; GlaxoSmithKline: Research Funding; Roche: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Gilead: Other: Travel, Accommodations, Expenses, Research Funding. Demirkan:Amgen: Consultancy. Fraser:Celgene: Research Funding; Janssen: Honoraria, Research Funding, Speakers Bureau. Bartlett:Pharmacyclics: Research Funding; Janssen: Research Funding. Dilhuydy:Gilead: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria. Loscertales:Roche: Honoraria, Speakers Bureau; Gilead Sciences: 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, Speakers Bureau. Goy:Genentech: Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Writing support, Speakers Bureau; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Ganguly:Seattle Genetics: Speakers Bureau; Janssen: Research Funding; Onyx: Speakers Bureau. Poggesi:Janssen: Employment, Equity Ownership. de Jong:Janssen: Employment. Neyens:Janssen: Employment. Salman:Janssen Research & Development: Employment, Equity Ownership, Other: Travel, Accommodations, Expenses. Howes:Janssen Research & Development: Employment. Mahler:Janssen Research & Development: Employment.

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Results from Phase 1/2 Trial of Tagraxofusp in Combination with Pomalidomide and Dexamethasone in Relapsed or Refractory Multiple Myeloma

Blood ◽

10.1182/blood-2019-130410 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3145-3145 ◽

Cited By ~ 1

Author(s):

Paul G. Richardson ◽

Myo Htut ◽

Cristina Gasparetto ◽

Jeffrey A. Zonder ◽

Thomas G. Martin ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Peripheral Blood ◽

Research Funding ◽

Phase 1 ◽

Single Agent ◽

Advisory Board ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership

Background: The bone marrow microenvironment of many multiple myeloma (MM) patients contains high levels of CD123-expressing plasmacytoid dendritic cells (pDCs). These pDCs have been shown to augment MM growth and contribute to drug resistance (Chauhan, et al., Cancer Cell, 2009). Tagraxofusp, a novel CD123 targeted therapy, has demonstrated high levels of anti-tumor activity in patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN), an aggressive CD123+ malignancy of pDC origin. Tagraxofusp demonstrated potent in vitro and in vivo activity against MM cell lines and primary tumor samples via both a direct anti-MM effect and indirect pDC-targeting effect (Ray, et al., Leukemia, 2017), as well as demonstrating synergy in these systems when used in combination with traditional MM therapies including pomalidomide (POM). As such, targeting pDCs with tagraxofusp may offer a novel therapeutic approach in MM. Methods: This multicenter, single arm Phase 1/2 trial enrolled patients with relapsed or refractory (r/r) MM and tested two different doses of tagraxofusp (7 or 9 mcg/kg). Patients received tagraxofusp as a daily IV infusion for days 1-5 of a 28-day cycle as a single agent for the initial run-in cycle (cycle 0) and in combination with standard doses/administration of POM and dexamethasone (DEX) in cycles 1 and beyond. Objectives included evaluation of safety and tolerability, identification of the maximum tolerated or tested dose, and efficacy. Results: 9 patients with r/r MM received tagraxofusp (7 mcg/kg, n=7; 9 mcg/kg, n=2). 5 males, median age 65 years (range: 57-70), median 3 prior therapies (range 2-6). Median follow-up was 12 months (range: 7 - 19). The most common treatment-emergent AEs (TEAEs) were hypoalbuminemia 67% (6/9); chills, fatigue, insomnia, nausea and pyrexia each 56% (5/9); and dizziness, headache, hypophosphatemia, and thrombocytopenia each 44% (4/9). The most common grade 3 and 4 TEAEs were thrombocytopenia 44% (4/9) and neutropenia 33% (3/9). No grade 5 events reported. 5 patients treated with tagraxofusp and POM+DEX had a partial response (PR) after tumor evaluation. These patients demonstrated a rapid decrease in a set of myeloma-related laboratory values from pre-tagraxofusp treatment levels after the first combination cycle of tagraxofusp and POM+DEX. Additionally, these 5 patients demonstrated >50% decreases in peripheral blood pDC levels after both tagraxofusp monotherapy and combination therapy. Conclusions: Tagraxofusp was well-tolerated, with a predictable and manageable safety profile, when dosed in combination with POM+DEX in patients with r/r MM. Evidence of pDC suppression in peripheral blood and BM was observed in this patient population. 5 patients that received tagraxofusp and POM+DEX combination had PRs and decreases in pDC levels while on treatment with tagraxofusp. Given CD123 expression on pDCs in the tumor microenvironment and the potential synergy of tagraxofusp with certain MM agents including POM, tagraxofusp may offer a novel mechanism of action in MM. NCT02661022. Disclosures Richardson: Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding. Gasparetto:Celgene: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Janssen: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; BMS: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed . Zonder:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees. Martin:Roche and Juno: Consultancy; Amgen, Sanofi, Seattle Genetics: Research Funding. Chen:Stemline Therapeutics: Employment, Equity Ownership. Brooks:Stemline Therapeutics: Employment, Equity Ownership, Patents & Royalties. McDonald:Stemline Therapeutics: Employment, Equity Ownership. Rupprecht:Stemline Therapeutics: Employment, Equity Ownership. Wysowskyj:Stemline Therapeutics: Employment, Equity Ownership. Chauhan:C4 Therapeutics.: Equity Ownership; Stemline Therapeutics: Consultancy. Anderson:Gilead Sciences: Other: Advisory Board; Janssen: Other: Advisory Board; Sanofi-Aventis: Other: Advisory Board; OncoPep: Other: Scientific founder ; C4 Therapeutics: Other: Scientific founder .

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