A Retrospective Analysis of Pneumocystis Jirovecii Pneumonia Infection in Patients Receiving Idelalisib in Clinical Trials

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3705-3705 ◽  
Author(s):  
Laurie H Sehn ◽  
Michael Hallek ◽  
Wojciech Jurczak ◽  
Jennifer R. Brown ◽  
Paul M. Barr ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Pneumocystis Jirovecii Pneumonia ◽  
Employment Equity ◽  
Advisory Committees ◽  
Increased Risk ◽  
Equity Ownership ◽  
Cd20 Antibody ◽  
Anti Cd20 ◽  
Support Research

Abstract Introduction: Opportunistic infections such as Pneumocystis jirovecii pneumonia (PJP) occur commonly in immunocompromised hosts such as patients (pts) with cancer (especially hematological malignancies such as chronic lymphocytic leukemia [CLL] and indolent non-Hodgkin lymphoma [iNHL]) or those receiving immunosuppressive therapies (such as steroids, chemotherapy). Recently, an increased risk of PJP infection was identified in 3 ongoing phase 3 studies evaluating idelalisib, administered in combination with the standard regimens rituximab (R) or bendamustine and rituximab (BR), in front-line CLL and early-line iNHL. Subsequently, a comprehensive analysis evaluating PJP infection across the clinical development program was performed to identify possible risk factors for developing PJP infection, including age, concomitant therapy (co-therapy) administered, geographic distribution of PJP infection, and regional use of prophylaxis. Methods: A retrospective analysis of 2198 pts receiving study treatment with idelalisib alone or in combination with co-therapy (anti-CD20 antibody or BR) and pts receiving only co-therapy (anti-CD20 ± bendamustine) (n = 1391 and 807, respectively) across 8 studies (frontline/relapsed CLL and relapsed iNHL) between 2010 and 2016 was performed. PJP infection was defined based on MedDRA high-level term of pneumocystis infections. In this analysis, other parameters were included for evaluation of risk of developing PJP infection-prophylaxis for PJP, geographic region, age, and CD4 count. Results: The overall incidence of PJP infection was 2.5% in pts on idelalisib ± co-therapy vs 0.2% in pts receiving only anti-CD20 antibody alone or BR alone (relative risk = 12.5). The median time to PJP event was 141 days since initiation of IDELA or co-therapy. The incidence of PJP infection was similar, irrespective of pt age. In the pt population receiving IDELA ± co-therapy - prophylaxis for PJP reduced the incidence of infection to 1.3% (from 3.4% in pts not receiving prophylaxis). Additionally, analysis by type of co-therapy received - the incidence of PJP infection was 2.2% vs 3.1% with IDELA + BR and IDELA + anti-CD20 alone respectively. A correlation between CD4 count (<200 cells/mcL) and an increased risk of PJP infection was not observed. Additional data are provided in Table 1. Conclusion: There is a small but increased risk of PJP infection during treatment with idelalisib within the clinical trial program. These data suggest that prophylaxis for PJP may reduce the risk of infection by as much as 60%. Administration of PJP prophylaxis is now recommended in all pts receiving treatment with idelalisib. Disclosures Sehn: roche/genentech: Consultancy, Honoraria; amgen: Consultancy, Honoraria; seattle genetics: Consultancy, Honoraria; abbvie: Consultancy, Honoraria; TG therapeutics: Consultancy, Honoraria; celgene: Consultancy, Honoraria; lundbeck: Consultancy, Honoraria; janssen: Consultancy, Honoraria. Hallek:Mundipharma: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; F. Hoffmann-LaRoche: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau. Jurczak:Gilead Sciences: Research Funding; Celltrion, Inc: Research Funding; Janssen: Research Funding; Bayer: Research Funding; Acerta: Research Funding. Brown:Infinity: Consultancy; Gilead Sciences: Consultancy; Janssen: Consultancy; Pfizer: Consultancy; Sun BioPharma: Consultancy; Celgene: Consultancy; Roche/Genentech: Consultancy; Abbvie: Consultancy. Barr:Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Consultancy. Catalano:Roche: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Membership on an entity's Board of Directors or advisory committees. Coutre:Gilead Sciences: Consultancy, Research Funding. Furman:Gilead Sciences: Consultancy; Pharmacyclics: Consultancy, Speakers Bureau; Janssen: Consultancy; Genentech: Consultancy; Abbvie: Consultancy, Honoraria. Lamanna:Gilead Sciences: Membership on an entity's Board of Directors or advisory committees, Research Funding. Zelenetz:Gilead Sciences: Research Funding. Sharman:Gilead Sciences, Inc.: Honoraria, Research Funding. Adewoye:Gilead Sciences: Employment, Equity Ownership. Kim:Gilead Sciences: Employment, Equity Ownership. Flinn:Janssen: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Gilead Sciences: Research Funding; ARIAD: Research Funding; RainTree Oncology Services: Equity Ownership. Salles:Gilead: Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria, Research Funding; Mundipharma: Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria.

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 ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4679-4679 ◽  
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.

Analysis of Pomalidomide Plus Low-Dose Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma with Vs without Moderate Renal Impairment

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3031-3031 ◽  
Author(s):  
David S Siegel ◽  
Katja C. Weisel ◽  
Meletios A. Dimopoulos ◽  
Rachid Baz ◽  
Paul G. Richardson ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Research Funding ◽  
Low Dose ◽  
Pooled Analysis ◽  
Employment Equity ◽  
Advisory Committees ◽  
Safety And Efficacy ◽  
Equity Ownership ◽  
Support Research

Abstract Introduction: Renal impairment (RI) occurs in ≈ 20% to 40% of patients (pts) with multiple myeloma (MM; Kastritis et al, Haematologica, 2007) and is a major comorbidity with this disease (Korbet et al, J Am Soc Nephrol, 2006). Pts with MM who relapse on or become refractory to treatment (Tx) experience shortened overall survival (OS; Kumar et al, Leukemia, 2012). Pomalidomide + low-dose dexamethasone (POM + LoDEX) is approved for the Tx of relapsed/refractory MM (RRMM) in pts who have had Tx failure with lenalidomide and/or bortezomib. POM + LoDEX demonstrated safety and efficacy in pts with RRMM (MM-010; Dimopoulos et al, EHA 2015) as well as extended progression-free survival (PFS) and OS vs high-dose dexamethasone (MM-003; San Miguel et al, Lancet Oncol, 2013) or POM alone (MM-002; Richardson et al, Blood, 2014). Each trial included pts with moderate RI, and this pooled analysis examines the safety and efficacy of POM + LoDEX in pts with moderate RI. Patients and Methods: Pts from MM-002, MM-003, and MM-010 who had received POM + LoDEX were grouped by RI status (with moderate RI [creatinine clearance (CrCl) ≥ 30 to < 60 mL/min] and without RI [CrCl ≥ 60 mL/min]) and assessed for safety and efficacy. Results: Overall, from the 3 trials, data from 356 pts with moderate RI and 716 pts without RI were analyzed. Pts with moderate RI were slightly older (70 vs 63 yrs) and more commonly had International Staging System stage III disease (45.8% vs 25.4% in the 271 and 544 pts with available data). Median time from diagnosis was similar, 5.2 yrs (with moderate RI) vs 5.3 years (without RI); pts in both subgroups had a median of 5 prior Tx. The proportions of pts with moderate RI vs without RI who were refractory to LEN (95.5% vs 93.0%), BORT (82.0% vs 80.7%), and both LEN and BORT (78.4% vs 76.1%) were similar. The median Tx duration was slightly shorter for pts with moderate RI vs without RI (16.6 vs 20.4 weeks), but the median average daily dose (4.0 mg/day) and median relative dose intensity (0.9) were the same between renal subgroups. There were similar frequencies of discontinuations (7.4% vs 5.8%), dose reductions (22.7% vs 21.1%), and interruptions (63.1% vs 63.5%) due to adverse events (AEs) between subgroups of pts with moderate RI vs without RI. The most common grade 3/4 AEs for pts with moderate RI vs without RI were neutropenia (45.5% vs 48.3%), anemia (34.9% vs 27.5%), infections (31.3% vs 32.3%), and thrombocytopenia (21.3% vs 22.6%). The frequency of deep vein thrombosis/pulmonary embolism or peripheral neuropathy was ≤ 2% in both subgroups. The overall response rate (ORR) was 32.0% vs 33.0%, the median PFS was 18.1 weeks (95% CI, 15.6-20.9 weeks) vs 21.1 weeks (95% CI, 19.0-24.3 weeks), and median time to progression (TTP) was 20.3 weeks (95% CI, 17.3-24.1 weeks) vs 24.0 weeks (95% CI, 20.1-25.6 weeks) in pts with vs without moderate RI, respectively. Consistent with the poor prognosis associated with RI, median OS was shorter for pts with moderate RI (45.6 weeks [95% CI, 37.9-50.1 weeks]) vs those without RI (62.7 weeks [95% CI, 54.9-70.3 weeks]). Conclusions: In a pooled analysis of 3 trials of pts with RRMM treated with POM + LoDEX, ORR, PFS, TTP, and tolerability results appeared to be independent of the presence or absence of moderate RI. This analysis supports the use of POM + LoDEX as a standard of care in RRMM for pts with or without moderate RI. Disclosures Siegel: Celgene Corporation: Speakers Bureau; Amgen: Speakers Bureau; Takeda: Speakers Bureau; Merck: Speakers Bureau; Novartis: Speakers Bureau. Weisel:Amgen: Consultancy, Honoraria, Other: Travel Support; Celgene: Consultancy, Honoraria, Other: Travel Support, Research Funding; Janssen Pharmaceuticals: Consultancy, Honoraria, Other: Travel Support, Research Funding; Novartis: Other: Travel Support; Onyx: Consultancy, Honoraria; Noxxon: Consultancy; BMS: Consultancy, Honoraria, Other: Travel Support. Dimopoulos:Genesis: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Onyx: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Janssen-Cilag: Honoraria. Baz:Karyopharm: Research Funding; Millennium: Research Funding; Celgene Corporation: Research Funding; Sanofi: Research Funding. Richardson:Bristol-Myers Squibb: 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; Millennium Takeda: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees. Delforge:Celgene Corporation: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Novartis: Honoraria. Song:Celgene Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. San Miguel:Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees. Moreau:Millennium: 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; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Yu:Celgene Corporation: Employment, Equity Ownership. Hong:Celgene Corporation: Employment, Equity Ownership. Sternas:Celgene Corporation: Employment, Equity Ownership. Zaki:Celgene Corporation: Employment, Equity Ownership. Palumbo:Novartis, Sanofi Aventis: Honoraria; Celgene, Millennium Pharmaceuticals, Amgen, Bristol-Myers Squibb, Genmab, Janssen-Cilag, Onyx Pharmaceuticals: Consultancy, Honoraria.

Baseline Laboratory Parameters Potentially Associated with Thrombophilia in Patients with Chronic ITP.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2191-2191
Author(s):  
Raymond S.M. Wong ◽  
Kalpana Bakshi ◽  
Andres Brainsky
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Protein S ◽  
Coagulation Cascade ◽  
Published Data ◽  
Employment Equity ◽  
Advisory Committees ◽  
Increased Risk ◽  
History Of ◽  
Equity Ownership

Abstract Abstract 2191 Background: The concept that chronic immune thrombocytopenia (cITP) may be pro-thrombotic has progressively gained acceptance as reports show an increased risk of thromboembolism (TEE) among cITP patients. A report from the Danish National Patient Registry showed an incidence of venous TEE of 5.32/1000 patient years (PYs) among cITP patients and 2.04/1000 PYs in a reference cohort (Severinsen 2010). Similar results were found in a US claims database study (Bennett 2008). ITP experts have gradually acknowledged this higher risk, but the reason for it is not understood. Many hematologic markers have been shown to be indicators of thrombophilia or activation of the clotting cascade (Jenkins 2012; De Stefano 2002; Tsai 2002); to our knowledge they have not been systematically and prospectively studied in cITP patients. Aim: Describe the frequency of potential laboratory predictors of thrombophilia in cITP. Methods: Adults with cITP were enrolled in an ongoing study to evaluate effects of eltrombopag on the bone marrow. A “thrombophilia panel” of suspected/known indicators of a thrombophilic state or activation of the coagulation cascade was collected at baseline. Patients could not have been treated with thrombopoietin receptor (TPO-R) agonists 6 months prior to enrollment. Patients with history of TEE and ≥2 risk factors for thrombosis were not eligible for enrollment. Results: Baseline thrombophilia panels were available for all 167 patients. Median age was 41 years; 108 (65%) patients were female. Approximately half of the patients were Caucasians (48.5%), while 31.1% and 19.2% had Central South and East Asian heritage. Median time since ITP diagnosis was 3.9 years (range, 0.2–45.7). Thirteen (8%) patients reported prior exposure to TPO-R agonists. Most patients (95%) had no family history of TEE and no patient had a history of TEE. Most patients (81%; Table 1) had abnormal levels of at least one well-known or suspected predictor of thrombosis or marker of activation of the coagulation cascade, and 93 (56%) had >1 abnormality. The most frequent abnormalities were elevated Factor VIII (48%), elevated d-dimer (32%), lupus anticoagulant (26%), and deficient protein S (22%; Table 2). Discussion: To our knowledge this is the only published prospective study of a thrombophilia profile in a cohort of cITP patients. Recently published data suggest that patients with cITP have a higher risk of TEE but no adequate explanation for this has been furnished. The fact that a high proportion of patients in this study had markers of thrombophilia or activation of clotting provides a working hypothesis that may at least partially elucidate this trait. Summary/conclusions: The multiple baseline abnormalities in possible predictors of thrombophilia may support the theory that ITP is pro-thrombotic, but they need to be assessed in and compared to the general population to allow proper understanding of their implications. The potential correlation of these abnormalities with TEE in this cohort will be reported upon study conclusion. Disclosures: Wong: GlaxoSmithKline: Research Funding; Pfizer: Research Funding; Biogen-Idec: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer: Consultancy, Research Funding; Johnson & Johnson: Research Funding; MSD: Research Funding; Roche: Research Funding; Bristol-Myers Squibb: Research Funding. Bakshi:GlaxoSmithKline: Employment, Equity Ownership. Brainsky:GlaxoSmithKline: Employment, Equity Ownership, Patents & Royalties.

scholarly journals Ibrutinib and Obinutuzumab in CLL: Improved MRD Response Rates with Substantially Enhanced MRD Depletion for Patients with >1 Year Prior Ibrutinib Exposure

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 181-181 ◽  
Author(s):  
Andy Rawstron ◽  
Talha Munir ◽  
Kristian Brock ◽  
Nichola Webster ◽  
Samuel Munoz Vicente ◽  
...  
Keyword(s):  
Adverse Events ◽  
Board Of Directors ◽  
Research Funding ◽  
Response Rate ◽  
Response Rates ◽  
Extension Study ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Anti Cd20 ◽  
Support Research

Abstract Background: Ibrutinib inhibits CLL cell proliferation and results in prolonged remission, but MRD responses are rare. Obinutuzumab is a second generation anti-CD20 monoclonal antibody that is effective in CLL and can result in MRD responses. In the IcICLLe study (ISRCTN12695354), 40 participants with CLL requiring treatment (20 treatment-naïve, 20 with relapsed/refractory [R/R] disease) received ibrutinib until complete remission with <0.01% Minimal Residual Disease (MRD) in the bone marrow or disease progression. The IcICLLe Extension Study expanded IcICLLe to examine the efficacy and safety of the combination of obinutuzumab and ibrutinib in 40 patients with R/R CLL, of which 10/40 had received prior ibrutinib on the IcICLLe trial. Initial results after 1 month of combination treatment indicated that adding obinutuzumab to ibrutinib improved CLL depletion, and 18 month follow-up data is now available. Aim: to determine the MRD response rates for patients with R/R CLL treated with ibrutinib and obinutuzumab in ibrutinib-naïve trial participants compared to those treated with >1 year prior ibrutinib. Patients: The IcICLLe Extension Study recruited 40 participants with relapsed/refractory CLL requiring treatment. They received continuous ibrutinib (420mg OD) with 6 cycles of obinutuzumab given over 6 months (M). Ten participants had >1 year of prior ibrutinib monotherapy in IcICLLe and 30 were ibrutinib-naïve with obinutuzumab started 24 hours after first ibrutinib dose. Patient characteristics and Adverse Events (AEs, collected from registration until 30 days after treatment cessation and reported at 1, 3, and 6M, and 6-monthly thereafter using the Common Terminology Criteria for Adverse Events v4.0) are shown in Table 1. MRD assessment was performed according to ERIC guidelines with a maximum detection limit of 0.001%/10-5. Results: In the 20 R/R patients treated with ibrutinib monotherapy there were no IWCLL CR/CRi responses and no patients achieved <0.01% CLL in the PB or BM at the 6 month response assessment. PB MRD levels either remained stable or improved at subsequent timepoints, with 1/20 achieving <0.01% PB MRD at 18M. The addition of obinutuzumab did not have a discernible impact on safety but was associated with a higher response rates and greater depth of MRD depletion than observed in patients treated with ibrutinib monotherapy, particularly in patients who had received ibrutinib for >1 year prior to combination with obinutuzumab (see Table 1). Patients receiving obinutuzumab after >1 year prior ibrutinib monotherapy achieved a higher response rate compared to ibrutinib-naive patients (IWCLL CR/CRi 50% vs. 30%), with a higher proportion of patients achieving <0.01% BM MRD (50% vs. 6%) and a greater depth of disease depletion (3.1 vs. 1.5 log reduction). PB MRD levels continued to improve in ibrutinib-naïve patients after cessation of obinutuzumab with 30% (9/30 with 4/30 inevaluable) achieving PB MRD <0.01% rate at 12 months post-obinutuzumab, compared to 60% (6/10 with 2/10 inevaluable) of patients at the same timepoint (12 months post-obinutuzumab) who had received ibrutinib for >1 year prior to starting obinutuzumab. The difference in extent of disease depletion observed with obinutuzumab may be related to the pre-obinutuzumab disease bulk because the majority of patients (7/10) with >1 year prior ibrutinib treatment had already resolved any lymphadenopathy prior to receiving obinutuzumab. Conclusions: The results suggest that the addition of obinutuzumab to ibrutinib may result in a substantial improvement in the depletion of CLL cells from the PB and BM for ibrutinib-naïve patients. However, a greater impact in MRD response rate and depth of depletion was seen when obinutuzumab was introduced after >1 year of ibrutinib treatment and tumour bulk was low. For patients with persistent disease during/ following pathway inhibition treatments, the addition of anti-CD20 antibody therapy may be effective at improving MRD response rates. Disclosures Rawstron: Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; BD Bio-sciences: Research Funding; Beckman Coulter: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Munir:MorphoSys: Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria; Novartis: Honoraria; Gilead: Honoraria; Janssen: Honoraria; Abbvie: Honoraria. Brock:GlaxoSmithKline: Equity Ownership; AstraZeneca: Equity Ownership; Merck Sharp Dohme: Other: Reimbursement of conference fees; Roche: Other: Reimbursement of expenses; Lilly: Honoraria. Pettitt:AstraZeneca: Research Funding; Celgene: Research Funding; Chugai: Research Funding; Roche: Research Funding; GSK/Novartis: Research Funding; Gilead: Research Funding; Napp: Research Funding. Fox:Celgene: Consultancy, Other: Travel support, Speakers Bureau; Janssen: Consultancy, Other: Personal fees and non-financial support, Speakers Bureau; Gilead: Consultancy, Other: Travel support, Research Funding, Speakers Bureau; AbbVie: Consultancy, Other: Travel support, Research Funding, Speakers Bureau; Roche: Consultancy, Other: Travel support, Research Funding, Speakers Bureau; Sunesis: Consultancy. Devereux:Janssen: Other: Personal fees; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Fegan:Janssen: Honoraria; Gilead Sciences, Inc.: Honoraria; Abbvie: Honoraria; Roche: Honoraria; Napp: Honoraria. Bloor:Janssen: Research Funding; AbbVie: Research Funding. Hillmen:Alexion Pharmaceuticals, Inc: Consultancy, Honoraria; Acerta: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Novartis: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Gilead Sciences, Inc.: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Rapid and Durable Responses with the SYK/JAK Inhibitor Cerdulatinib in a Phase 2 Study in Relapsed/Refractory Follicular Lymphoma-Alone or in Combination with Rituximab

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3981-3981
Author(s):  
Stephen D. Smith ◽  
Javier Munoz ◽  
Don Stevens ◽  
Sonali M. Smith ◽  
Tatyana A. Feldman ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Single Agent ◽  
Employment Equity ◽  
Advisory Committees ◽  
Prior Therapy ◽  
Equity Ownership ◽  
Grade 3 ◽  
Anti Cd20 ◽  
Age Range

Background: Despite recent advances, follicular lymphoma (FL) remains incurable for most patients. Relapsed/refractory (r/r) FL is associated with decremental treatment responses, accumulating toxicity, and poor survival among early failures of 1st line chemoimmunotherapy. Underscored by the recent approvals of idelalisib, copanlisib, and duvelisib, targeting B-cell receptor (BCR) signaling produces ORR of ~50% in r/r patients; however, new agents with a better therapeutic index over long-term administration are needed. SYK is a key regulator of BCR signaling (upstream of BTK and PI3K), and its inhibition results in clinical activity in FL. Compared with unaffected nodes, lymph nodes from FL patients have greater numbers of follicular helper T cells that express high levels of IL-4, which may support the tumor via the JAK1/3 pathway. Cerdulatinib, an oral, reversible inhibitor of SYK and JAK kinases (JAK1, JAK3, TYK2), previously reported a ~45% overall response rate (ORR) in r/r FL as a single agent. Xenograft studies suggest cerdulatinib may combine with rituximab to enhance antitumor activity. We report updated results from a phase 2a study of single-agent cerdulatinib and initial results in combination with rituximab in r/r FL. Methods: This phase 2a study confirmed the safety and efficacy of cerdulatinib 30 mg BID in r/r B- and T-cell lymphoma patients. Dose reductions were permitted to 15 mg BID. Response was assessed by Lugano criteria. Results: A planned interim analysis was performed on July 18, 2019, in which enrollment was 40 patients in the single-agent cohort and 19 patients in the rituximab combination cohort. For the single-agent cohort, median age (range) was 64 (42-81) years and median prior therapies (range) was 3 (1-9). Ninety-five percent of patients had prior anti-CD20 therapy, and 25% had prior therapy with BCR pathway inhibitors. For the combination cohort, median age (range) was 67 (47-85) years and median prior therapies (range) was 3 (1-10). Eighty-eight percent of patients had prior anti-CD20 therapy, and 32% had prior therapy with BCR pathway inhibitors. The safety profile appeared similar in both cohorts. The most common treatment-emergent grade 3+ adverse events in ≥5% of patients for both cohorts were lipase increase (27%), neutropenia (18%), diarrhea (12%), amylase increase (10%), hypertension (8%), nausea (7%), and pneumonia (5%). Grade 3+ infections occurred in 17.5% of single-agent cohort patients and 15.8% of combination cohort patients. Amylase and lipase increases generally were not associated with abdominal pain or pancreatitis. In addition, to date there has been no evidence of cumulative toxicity. The ORR was 45% as a single agent (12.5% complete response [CR], 32.5% partial response [PR], with 25% stable disease [SD] and 5% progressive disease [PD] in 40 evaluable patients) and 59% in the combination cohort (11.7% CR, 47% PR, with 27.8% SD and no PD in 17 evaluable patients). Responses typically occurred after 2 cycles, generally improved over time, and were durable in the single-agent cohort, with 10 patients on drug for >1 year. Enrollment in the combination cohort is ongoing. Updated safety and efficacy will be presented. Conclusion: The recommended cerdulatinib phase 2 dose of 30 mg BID was tolerable and efficacious in heavily pretreated r/r FL. The cerdulatinib + rituximab combination appears to be well tolerated, with tumor reductions in all evaluable patients. The safety profile and unique mechanism of action of cerdulatinib support further combination studies in FL. Disclosures Smith: Pharmacyclics: Research Funding; Denovo Biopharma: Research Funding; Portola Pharmaceuticals: Research Funding; Seattle Genetics: Research Funding; Acerta Pharma BV: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte Corporation: Research Funding; Genentech: Research Funding; Bristol-Myers Squibb (spouse): Research Funding; Ignyta (spouse): Research Funding; Ayala (spouse): Research Funding; Merck Sharp & Dohme Corp: Consultancy, Research Funding. Munoz:AstraZeneca: Speakers Bureau; Pharmacyclics LLC an AbbVie Company: Consultancy, Research Funding, Speakers Bureau; Kite Pharma: Consultancy, Research Funding, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Fosunkite: Speakers Bureau; Kyowa: Consultancy, Honoraria, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; Portola: Research Funding; Incyte: Research Funding. Stevens:Astellas: Consultancy. Smith:Portola Pharmaceuticals: Research Funding. Feldman:Kite Pharma: Honoraria, Other: Travel expenses, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Honoraria, Other: Travel expenses, Speakers Bureau; Pharmacyclics: Honoraria, Other: Travel expenses, Speakers Bureau; AbbVie: Honoraria, Other: Travel expenses, Speakers Bureau; Viracta: Research Funding; Trillium: Research Funding; Roche: Research Funding; Amgen: Research Funding; Cell Medica: Research Funding; Roche: Research Funding; Corvus: Research Funding; Eisai: Research Funding; Kyowa Hakko Kirin: Research Funding; Pfizer: Research Funding; Portola Pharma: Research Funding; Celgene: Honoraria, Research Funding, Speakers Bureau. Ye:MingSight: Research Funding; Janssen: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding; Onyx: Research Funding; Celgene: Research Funding; Takeda: Research Funding; AbbVie: Research Funding; Portola Pharmaceuticals: Research Funding. de Vos:Verastem: Consultancy; Portola Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy. Miller:Verastem: Consultancy, Honoraria, Research Funding, Speakers Bureau; Incyte: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Takeda: Honoraria, Research Funding, Speakers Bureau. Birrell:Portola Pharmaceuticals: Employment, Equity Ownership. Leeds:Portola Pharmaceuticals: Employment, Equity Ownership. Coffey:Portola Pharmaceuticals: Employment, Equity Ownership, Research Funding. Conley:Portola Pharmaceuticals: Employment, Equity Ownership. Michelson:Portola Pharmaceuticals: Employment, Equity Ownership. Curnutte:Portola Pharmaceuticals: Employment, Equity Ownership.

scholarly journals Results from a Phase 3, Multicenter, Non-Inferiority Study of Ravulizumab (ALXN1210) Versus Eculizumab in Adult Patients with Paroxysmal Nocturnal Hemoglobinuria Currently Treated with Eculizumab

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 625-625
Author(s):  
Austin G. Kulasekararaj ◽  
Anita Hill ◽  
Scott T. Rottinghaus ◽  
Saskia Langemeijer ◽  
Richard A. Wells ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Percentage Change ◽  
Employment Equity ◽  
Phase 3 ◽  
Advisory Committees ◽  
Fatigue Score ◽  
Large Phase ◽  
Equity Ownership ◽  
Support Research

Abstract Introduction Ravulizumab, an innovative complement C5 inhibitor given every 8 weeks (q8w), was recently demonstrated in a large phase 3 study of patients (pts) with paroxysmal nocturnal hemoglobinuria (PNH) and naïve to complement inhibitor therapy to be non-inferior to eculizumab given every 2 weeks (q2w) across all endpoints that measured different aspects of PNH disease (transfusion avoidance [TA], lactate dehydrogenase normalization [LDH-N], percent LDH reduction, breakthrough hemolysis [BTH], Functional Assessment of Chronic Illness Therapy [FACIT]-Fatigue, and hemoglobin stabilization [HGB-S]) (Lee JW et al. EHA Learning Center, Jun 17, 2018; LB2603). PNH pts currently receiving eculizumab may experience treatment burden associated with the q2w dosing regimen. With the development of ravulizumab, PNH pts on prior eculizumab therapy can potentially switch to ravulizumab without interruption of treatment. The primary objective of this study was to assess the noninferiority of ravulizumab compared to eculizumab in adult PNH pts who were clinically stable after having been treated with eculizumab for at least 6 months. Methods In this phase 3, open-label, multicenter study (NCT03056040), adult pts with a documented diagnosis of PNH who were treated with labelled-dose eculizumab for >6 months having LDH levels ≤1.5 times the upper limit of normal at screening were randomly assigned 1:1 to continue eculizumab or switch to ravulizumab. Pts randomized to ravulizumab received weight-based loading [day 1]/maintenance doses [day 15 and q8w thereafter]: ≥40 to <60 kg body weight [2400/3000mg]; ≥60 to <100 kg [2700/3300mg]; ≥100 kg [3000/3600mg]) through day 183 (primary completion date). Pts randomized to eculizumab received 900mg q2w. All pts must have received vaccination against N. meningitidis. Primary efficacy endpoint was hemolysis, as measured by percentage change in LDH levels from baseline (BL) to day 183. Non-inferiority was declared if the upper bound of the 95% confidence interval (CI) for the difference in change of LDH from BL (ravulizumab-eculizumab) was <15%. Key secondary efficacy endpoints tested in a hierarchal manner were proportion of patients with BTH, change in quality of life assessed by FACIT-Fatigue score, TA (percentage of pts remaining transfusion-free), and proportion of pts with HGB-S from BL to day 183. Change from BL in free C5 level over time was also assessed. Results Of 208 pts screened, 197 pts were randomized (1:1) to ravulizumab or eculizumab, 195 received treatment (ravulizumab, n=97; eculizumab, n=98), and 191 pts completed 183 days of treatment. Pt demographics and baseline clinical characteristics were similar between treatment groups. On average, pts had received prior eculizumab therapy for 5.8 years. All pts received all planned infusions of study medication. Ravulizumab was statistically significantly noninferior to eculizumab for the primary and all key secondary endpoints, with all point estimates favoring ravulizumab: percentage change in LDH levels (difference of -9.21% [95% CI: -18.84, 0.42]), BTH (difference of -5.1 [95% CI -18.89, 8.89]), change in FACIT-Fatigue score (difference of 1.47 [-0.21, 3.15]), TA (difference of 5.5 [95% CI -4.27, 15.68]), and HGB-S (difference of 1.4 [-10.41, 13.31]) (Fig A, Fig B). Superiority testing of the primary endpoint (percentage change in LDH) did not reach statistical significance (P=0.0583 vs P<0.05 required). Complete inhibition of serum C5 (mean free C5 serum of <0.5 µg/mL) was observed by the end of the first ravulizumab infusion and was sustained throughout the treatment period (Fig C). The most frequently reported adverse event was headache (26.8% versus 17.3% for ravulizumab and eculizumab, respectively). There were no meningococcal infections or discontinuations due to adverse events. Conclusion Results of this large phase 3 study show that ravulizumab achieved noninferiority compared with eculizumab in pts with PNH on stable eculizumab therapy. Pts can be safely and effectively switched from eculizumab given q2w to ravulizumab given q8w. In pts previously stable on eculizumab, no pts switched to ravulizumab experienced BTH vs 5 pts on eculizumab during the 26-week treatment period. This may be related to optimized ravulizumab dosing compared to eculizumab, resulting in complete and sustained C5 inhibition for all pts. Figure. Figure. Disclosures Kulasekararaj: Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Other: Travel Support . Hill:Apellis: Consultancy, Honoraria; Bioverativ: Consultancy, Honoraria; Regeneron: Consultancy, Honoraria; Akari: Consultancy, Honoraria; Ra Pharma: Consultancy, Honoraria; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria. Rottinghaus:Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership. Wells:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Alexion Pharmaceuticals, Inc.: Honoraria, Other: Travel Support , Research Funding. Gonzalez-Fernandez:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria. Gaya:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria. Lee:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding. Ojeda Gutierrez:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria. Szer:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Other: Travel Support , Research Funding. Risitano:Pfizer Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amyndas Pharmaceuticals: Consultancy; Alnylam Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ra Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding. Nakao:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria; Kyowa Hakko Kirin Co., Ltd.: Honoraria; Novartis: Honoraria. Bachman:Alexion Pharmaceuticals, Inc.: Equity Ownership, Other: Former employee. Shafner:Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership. Damokosh:Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership. Ortiz:Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership. Röth:Pfizer: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Bioverativ: Consultancy, Honoraria; Amgen: Research Funding. Peffault De Latour:Pfizer Inc.: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Amgen Inc.: Research Funding.

scholarly journals A Phase 2 Study of REGN1979, an Anti-CD20 x Anti-CD3 Bispecific Antibody (Ab), in Patients with Relapsed/Refractory (R/R) B-Cell Non-Hodgkin Lymphoma (B-NHL)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4007-4007
Author(s):  
Max S. Topp ◽  
Johannes Duell ◽  
Jingjin Li ◽  
Vladimir Jankovic ◽  
Israel Lowy ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Board Of Directors ◽  
Systemic Therapy ◽  
Research Funding ◽  
Phase 2 ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Anti Cd20

Background NHL is the most common hematological malignancy. Among a heterogeneous group of NHLs, 85-90% are of B-cell origin and include follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), and several other B-NHLs. Anti-CD20 Abs in combination with chemotherapy are the standard of care for the treatment of B-NHLs; however, despite initial responses, many patients relapse, often with progressively shorter response durations in subsequent lines of therapy and poor outcome. REGN1979 is a CD20 x CD3 bispecific IgG4 Ab that binds to CD3+ T-cells and CD20+ B-cells, targeting CD20+ tumor cells via T-cell-mediated cytotoxicity. An ongoing Phase 1 study in patients with B-cell malignancies is evaluating the safety, tolerability, and efficacy of REGN1979 as monotherapy (NCT02290951). Preliminary data from the Phase 1 study showed broad antitumor activity with REGN1979 in heavily pretreated R/R B-NHL patients, including some with progression after prior chimeric antigen receptor T (CAR T)-cell therapy. REGN1979 has been tolerated at doses up to 320 mg weekly, with no observed dose limiting toxicities. These data informed the dosage regimen of the current Phase 2 study. Methods This open-label, multi-center, Phase 2 study (NCT03888105) is evaluating the efficacy and safety of REGN1979 in six disease-specific cohorts, each comprising a single arm with independent parallel enrollment: patients with R/R FL Grade 1-3a after ≥2 prior lines of systemic therapy, including an anti-CD20 antibody and an alkylating agent; patients with R/R DLBCL after ≥2 prior lines of systemic therapy (patients in this cohort may not have received prior CAR T-cell therapy); patients with R/R DLBCL after CAR T-cell therapy failure; patients with MCL that have relapsed after or are refractory to Bruton's tyrosine kinase (BTK) inhibitor therapy (patients with R/R MCL who have demonstrated intolerance to BTK inhibitor therapy may also be enrolled); patients with R/R MZL that have relapsed after or are refractory to ≥1 prior line of systemic therapy; patients with R/R other B-NHL subtypes, excluding Waldenström macroglobulinemia, after ≥1 prior line of systemic therapy including an anti-CD20 antibody. The initial screening period of up to 28 days is followed by a weekly dosing period where REGN1979 is administered in gradually increasing doses to achieve target nominal dose by Week 4 and continued through Week 12. Patients then receive REGN1979 every two weeks for up to 86 weeks (total treatment period of 98 weeks). The post-treatment follow-up period will continue for up to 96 weeks after the last dose of study treatment. Approximately 481 patients will be enrolled at sites across the US, Canada, Europe, and the Asia-Pacific region. Key eligibility criteria are: age ≥18 years; ≥1 bi-dimensionally measurable nodal lesion of ≥1.5 cm; Eastern Cooperative Oncology Group performance status of 0 or 1; and adequate bone marrow and hepatic functions. Key exclusion criteria include primary central nervous system (CNS) lymphoma or involvement by non-primary CNS NHL; treatment with systemic anti-lymphoma therapy within five half-lives or 28 days prior to first administration of REGN1979; and history of allogeneic hematopoietic stem cell transplantation. The primary endpoint for each disease-specific cohort is objective response rate (ORR) according to the Lugano Classification of response in malignant lymphoma by independent central review. Secondary endpoints include complete response (CR) rate, progression-free survival, duration of response, disease control rate (DCR), duration of disease control, overall survival; incidence and severity of treatment-emergent adverse events; patient-reported outcomes; pharmacokinetics; and immunogenicity responses. The primary endpoint, ORR, will be summarized along with a two-sided 95% confidence interval (CI). Other efficacy endpoints, such as CR rate and DCR, will be summarized using the same approach as for ORR. The time to event endpoints will be summarized, where appropriate, by median and the corresponding 95% CI using the Kaplan-Meier method. The study is recruiting in FL grade 1-3a cohort and recruitment in other disease-specific cohorts is planned. Disclosures Topp: Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Regeneron Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Duell:Regeneron Pharmaceuticals, Inc.: Research Funding. Li:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Jankovic:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Lowy:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Sternberg:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Adriaens:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Peterman:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Ambati:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Bannerji:AbbVie, Inc: Consultancy, travel support; Celgene: Consultancy; Pharmacyclics: Other: travel support; Pharmacyclics: Other: travel support; Gilead: Other: travel support; Gilead: Other: travel support; AbbVie, Inc: Consultancy; Merck: Other: travel support, Patents & Royalties: IP rights; Celgene: Consultancy; Regeneron Pharmaceuticals, Inc.: Consultancy, Other: travel support, Research Funding; Regeneron Pharmaceuticals, Inc.: Consultancy, Other: travel support, Research Funding; Merck: Other: travel support, Patents & Royalties: IP rights. OffLabel Disclosure: The abstract outlines data on the use of REGN1979 in a Phase 1 trial in patients with relapsed/refractory B-cell non-Hodgkin lymphoma and describes the design of a Phase 2 trial in a similar patient population.

scholarly journals Association of Bleeding Severity with Mortality with in-Hospital and Extended Thromboprophylaxis in the Medically Ill in the Magellan Trial

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2441-2441
Author(s):  
Alex C. Spyropoulos ◽  
Gary E. Raskob ◽  
Alexander T Cohen ◽  
Walter Ageno ◽  
Jeffrey I. Weitz ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Board Of Directors ◽  
Major Bleeding ◽  
Research Funding ◽  
Bleeding Events ◽  
Employment Equity ◽  
Advisory Committees ◽  
Increased Risk ◽  
Bayer Healthcare ◽  
Equity Ownership

Background: Venous thromboembolism (VTE) is common after hospitalization in acutely ill medical patients, yet extended thromboprophylaxis has not been widely implemented due to concerns about bleeding. The MAGELLAN study (NCT00571649) evaluated whether rivaroxaban (10 mg QD for 35±4 days) compared with enoxaparin (40 mg QD for 10±4 days) followed by placebo could prevent asymptomatic deep vein thrombosis, symptomatic VTE, and VTE-related death. Through Day 35, rivaroxaban was superior to enoxaparin/placebo in the modified intent-to-treat population (4.4% vs 5.7%, RR 0.77, 95%CI, 0.62 to 0.96, p=0.02), but there was an increase in clinically relevant bleeding, the composite of major and non-major clinically relevant (NMCR) bleeding (4.1% vs 1,7%, RR 2.5, 95%CI 1.85-3.25, p<0.001). Although major bleeding has been associated with increased mortality, the relationship between NMCR bleeding and all-cause mortality (ACM) is not established. We hypothesized that subjects in the MAGELLAN trial with major bleeding but not those with NMCR bleeding, would be at an increased risk of ACM irrespective of treatment group. Methods: We evaluated all bleeding events in subjects taking at least one dose of study drug from randomization until 2 days after the last dose (safety population) and their association with ACM through the Day 90 visit in 3 mutually exclusive groups: (1) subjects with no major or NMCR bleeding; (2) subjects whose first event was NMCR bleeding; and (3) subjects whose first event was major bleeding. Subjects only developing minimal or trivial bleeding were grouped with those who had no clinically relevant bleeding. Using a Cox proportional hazards model that included the bleeding group variable and baseline covariates significantly associated with ACM at p<0.05 (age, BMI, history of cancer, history of anemia, inflammatory disease, acute ischemic stroke, and acute respiratory insufficiency), we compared the risk of ACM in subjects with and without bleeding events. Results: The incidence of ACM for subjects who had NMCR bleeding was numerically higher but not significantly increased compared with subjects with no bleeding (20/176, 11.4% vs 468/7763, 6.0%, HR 1.41 95%CI 0.88, 2.25, p=0.151), while subjects with major bleeding were at a significantly increased risk of death (28/59, 47.5% vs 468/7763, 6.0%, HR 7.74 95%CI 5.16, 11.59, p<0.0001). Results of landmark analyses from the first bleeding event or end of treatment + 2 days to ACM for the three groups are displayed (Figure). Limitations: This analysis was post hoc and may have been underpowered to detect differences in ACM associated with NMCR bleeding. Conclusion: Major bleeding was associated with a significantly increased risk of ACM but NMCR bleeding was not. This suggests that a modest increase in NMCR bleeding associated with extended thromboprophylaxis with rivaroxaban may be acceptable to prevent VTE. Strategies to better select patients at lower risk of bleeding may improve the benefit risk profile of extended thromboprophylaxis with rivaroxaban. Disclosures Spyropoulos: Daiichi Sankyo: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding; Portola: Consultancy; Bayer Healthcare: Consultancy; ATLAS (Colorado Prevention Center): Consultancy; Janssen R&D, LLC: Consultancy. Raskob:Janssen R&D, LLC: Consultancy, Honoraria; Novartis: Consultancy; Tetherex: Consultancy; Daiichi Sankyo: Consultancy, Honoraria; Anthos: Consultancy; Boehringer Ingelheim: Consultancy; Pfizer: Consultancy, Honoraria; Portola: Consultancy; Bayer Healthcare: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Eli Lilly: Consultancy. Cohen:Boston Scientific: Consultancy; CSL Behring: Consultancy; GlaxoSmithKline: Consultancy, Speakers Bureau; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Boehringer-Ingelheim: Consultancy, Speakers Bureau; GLG: Consultancy; AbbVie: Consultancy; ACI Clinical: Consultancy; Aspen: Consultancy, Speakers Bureau; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Guidepoint Global: Consultancy; Johnson and Johnson: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Leo Pharma: Consultancy; Medscape: Consultancy, Speakers Bureau; McKinsey: Consultancy; Navigant: Consultancy; ONO: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Temasek Capital: Consultancy; TRN: Consultancy; UK Government Health Select Committee: Other: advised the UK Government Health Select Committee, the all-party working group on thrombosis, the Department of Health, and the NHS, on the prevention of VTE; Lifeblood: Other: advisor to Lifeblood: the thrombosis charity and is the founder of the European educational charity the Coalition to Prevent Venous Thromboembolism. Ageno:Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees, Other: conference and travel support; Bayer: Membership on an entity's Board of Directors or advisory committees, Other: research support,travel support ; BMS Pfizer: Other: travel support; Aspen: Membership on an entity's Board of Directors or advisory committees, Other: travel support; Portola: Membership on an entity's Board of Directors or advisory committees, Other: travel support; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees, Other: travel support; Sanofi: Membership on an entity's Board of Directors or advisory committees, Other: travel support. Weitz:Janssen R&D, LLC: Consultancy; Bayer Healthcare: Consultancy, Honoraria; Boehringer Ingelheim: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Daiichi-Sankyo: Consultancy, Honoraria; Ionis: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Portola: Consultancy, Honoraria. Spiro:Bayer U.S. LLC: Employment, Equity Ownership. Lu:Janssen R&D, LLC: Employment, Equity Ownership. Lipardi:Janssen Research and Develompent: Employment, Equity Ownership. Barnathan:Janssen Research and Development LLC: Employment, Equity Ownership. OffLabel Disclosure: Rivaroxaban is a Factor Xa inhibitor. It is currently under review by FDA for approval as thromboprophylaxis in acutely ill medical patients at risk for venous thromboembolism.

Ofatumumab Versus Rituximab Salvage Chemoimmunotherapy in Relapsed or Refractory Diffuse Large B-Cell Lymphoma: The Orcharrd Study (OMB110928)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 630-630 ◽  
Author(s):  
Gustaaf W van Imhoff ◽  
Andrew McMillan ◽  
Matthew J. Matasar ◽  
John Radford ◽  
Kirit M Ardeshna ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
B Cell Lymphoma ◽  
Salvage Treatment ◽  
High Dose ◽  
First Line ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Anti Cd20

Abstract Background: Salvage chemoimmunotherapy, followed by high-dose therapy and autologous stem cell transplantation (ASCT) for responding patients, is standard treatment for fit patients with diffuse large B-cell lymphoma (DLBCL) failing first line rituximab-CHOP treatment. Response to salvage treatment is critical for a durable progression free survival (PFS) following ASCT. The 3-year event free survival (EFS) for patients treated with rituximab (R) in first-line regimens who received salvage chemotherapy in combination with R was only 21% (ref-1). The anti-CD20 monoclonal antibody ofatumumab (O) has shown efficacy in R resistant lymphoma cell lines and in patients with relapsed or refractory intermediate grade lymphoma when combined with chemotherapy (ref-2). In this randomised phase III study we compared the efficacy of O versus R in combination with DHAP (cisplatin, cytarabine, dexamethasone), aiming to improve PFS following salvage treatment and ASCT (NCT01014208). Methods: CD20+ DLBCL patients, aged ≥18y, in first relapse or not responding (<CR) to first-line R-CHOP-like treatment, with FDG-PET positive measurable disease, were randomised 1:1 between 3 cycles of R-DHAP or O-DHAP. Randomisation was stratified for risk factors: relapse >1y vs ≤1y (including PR, SD or PD) and secondary age adjusted IPI (sAAIPI) 0-1 vs 2-3. Either O 1000 mg or R 375 mg/m2was administered for a total of 4 infusions on days 1 and 8 of cycle 1, and day 1 of cycles 2 and 3 of DHAP. DHAP was dosed as published (ref 1). Peripheral blood stem cells (PBSC) were harvested during cycle 2 or 3. Responding patients (PR+CR) after 2 cycles received the third cycle followed by high-dose therapy and ASCT. Response after 2 cycles was determined by CT scans, and response after 3 cycles and 3 months after ASCT was determined by combined CT+FDG-PET scans according to RRCML criteria by an independent review. Patients with SD after cycle 2 or progressive disease did not proceed to ASCT. The primary endpoint was PFS, defined as time from randomisation to SD after cycle 2, PD or death, whichever came first. EFS included new therapy as an event in addition to the definitions for PFS. Results: Between March 2010 and December 2013, 447 patients were randomised: 222 O-DHAP, 225 R-DHAP. Two patients in the R-DHAP arm were excluded from the ITT-population in accordance with the protocol because they did not receive any study treatment. The database cut-off date was Feb 28, 2014. Patient characteristics were evenly distributed between study arms: median age 57y (range, 18-83); 39% ≥60y; male 61%; Caucasian 72%; LDH >ULN 49%; ECOG PS >1 8%; stage III/IV 63%; sAAIPI 2-3 40%; and response to first line therapy: CR >1y 29%, CR ≤1y 11%, PR 36%, SD 8%, PD 16%. PFS, EFS and OS were not significantly different in the O-arm vs R-arm: PFS-2y 21% vs 26% (HR 1.14, 95% CI 0.90-1.45, p=0.27); EFS-2y 14% vs 17% (HR 1.12, p=0.27); OS-2y 41% vs 36% (HR 0.86, p=0.25). sAAIPI and response duration after first-line treatment were risk factors significantly associated with PFS and OS. In all, 102 (46%) patients in the O-arm and 113 (51%) in the R-arm died, 79% due to disease progression. Response to salvage was not significantly different between the study arms; ORR: O-arm 38% (CR 15%) vs R-arm 42% (CR 22%). ASCT on protocol was completed by 74 (33%) patients in the O-arm and 81 (36%) in the R-arm. Off protocol SCT was completed by 37 (17%) patients in the O-arm and 26 (12%) in the R-arm. No major differences in clinically relevant toxicity were observed between the arms. Rash (22% vs 9%) and raised serum creatinine (24% vs 16%) were increased in the O-arm. Time to neutrophil (ANC >0.5x109/L and increasing) and platelet (PLT >10x109/L and increasing) recovery after each cycle of DHAP therapy, and PBSC harvest, did not differ between the arms. Time to engraftment (PLT ≥20x109/L and 3 consecutive days of ANC ≥0.5x109/L, prior to day 42) after ASCT was shorter in the R-arm vs the O-arm (HR 0.62, p=0.05). Conclusion: In this large international study no difference in efficacy was found between ofatumumab and rituximab in combination with DHAP as salvage treatment for refractory or relapsed DLBCL. Improved treatment for patients failing first line R-CHOP treatment is urgently needed. Ref 1: Gisselbrecht, J Clin Oncol; 2010:28:4184 Ref 2: Matasar, Blood; 2013 122: 499 Disclosures Off Label Use: Ofatumumab is an anti-CD20 monoclonal antibody. Ofatumumab is not indicated in DLBCL. Matasar:Genentech, Merck: Membership on an entity's Board of Directors or advisory committees. Radford:Millennium, Seattle Genetics, Cell Medica: Consultancy, Equity Ownership, Honoraria, Research Funding, Speakers Bureau, Wife is a GSK/AZ Share Holder Other. Ardeshna:Roche, Gilead, Millenium: Consultancy, Honoraria, Speakers Bureau. Kim:Novartis, Takeda, Celgene: Research Funding. Hong:Fudan University Shanghai Cancer Center: Employment. Davies:Hoffman LaRoche, GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ogura:GlaxoSmithKline Jansen Pharma Takeda, Eisai, Symbio, Zenyakuu, Pfizer, Chugai, Celgene, Astra Zeneca, Mundi, Sorasia, GSK, Takeda: Honoraria, Research Funding. Fennessy:GlaxoSmithKline: Employment, Equity Ownership. Liao:GlaxoSmithKline: Employment, Equity Ownership. Lisby:Genmab: Employment. Lin:GlaxoSmithKline: Employment, Equity Ownership. Hagenbeek:Milennium, Genmab: Membership on an entity's Board of Directors or advisory committees.

scholarly journals A Phase 1 Study of Flotetuzumab, a CD123 x CD3 DART® Protein, Combined with MGA012, an Anti-PD-1 Antibody, in Patients with Relapsed or Refractory Acute Myeloid Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2662-2662 ◽  
Author(s):  
Andrew H. Wei ◽  
Chun Yew Fong ◽  
Pau Montesinos ◽  
Maria Calbacho ◽  
Jordi Sierra Gil ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Phase 1 ◽  
Research Support ◽  
Employment Equity ◽  
Phase 1 Study ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Support Research

Background Acute myeloid leukemia (AML) blasts and leukemic stem and progenitor cells typically express higher levels of CD123 than their normal hematopoietic stem cell counterparts, making CD123 an attractive target. Leukemic CD123 expression is associated with poor prognosis, high-risk disease, and increased risk of induction failure (Vergez et al 2011). Single-agent flotetuzumab, an investigational CD123 x CD3 bispecific DART protein, has shown evidence of clinical activity in a Phase 1 study of relapsed/refractory (R/R) acute myeloid leukemia (AML). In this study, flotetuzumab led to T-cell activation which in turn was associated with PD-1 induction on T lymphocytes, enhanced IFNɣ secretion, and upregulation of PD-L1 expression by AML blasts (ASH 2018 Rutella, ASH 2018 Uy). In vitro studies have shown synergistic T-cell mediated cytotoxicity of an AML cell line (KG1A) with flotetuzumab in the presence of PD-1/PD-L1 axis blockade compared to flotetuzumab alone. MGA012, also known as INCMGA00012, is an investigational anti-PD-1 antibody that has shown clinical activity in a Phase 1 study (SITC 2018 Mehnert). We hypothesize that combined checkpoint inhibition with MGA012 together with redirected T‐cell killing of CD123+ cells with flotetuzumab may show enhanced activity over flotetuzumab alone. Methods This is a Phase 1 dose escalation study designed to characterize the safety, tolerability, dose-limiting toxicities, maximum tolerated dose (MTD) or maximum administered dose (if no MTD is defined), pharmacokinetics, and preliminary anti-leukemic activity of flotetuzumab in combination with MGA012, each administered intravenously (IV) in patients with R/R AML. Response evaluation will be determined by modified ELN 2017 criteria. Activity is measured by complete response (CR) (complete remission [CR], or CR with partial hematologic recovery [CRh], or CR with incomplete hematological recovery [CRi], or morphologic leukemia-free state [MLFS]) rate, relapse-free survival, or mortality rate at 1 and 3 months. The impact of flotetuzumab/MGA012 combination on overall survival and event-free survival will be explored. Eligible patients will consist of adults with relapsed or refractory AML (any subtype except acute promyelocytic leukemia) who have exhausted standard of care options. In Induction Cycle 1, patients will be treated with a step-up lead in dose of flotetuzumab, followed by continuous infusion flotetuzumab, starting at week 2 of Cycle 1 and continuing through each 28-day cycle. MGA012 will be administered every two weeks. Depending on response, patients will transition to either consolidation or second induction. Eligible patients who achieve CR/CRh/CRi can receive maintenance MGA012 alone for up to 12 months. Disclosures Wei: AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: AHW is a former employee of the Walter and Eliza Hall Institute and receives a fraction of its royalty stream related to venetoclax, Research Funding, Speakers Bureau; Astellas: 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, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Macrogenics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Honoraria, Research Funding; Janssen: Honoraria. Fong:Novartis: Speakers Bureau; Amgen: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Astellas: Consultancy. Montesinos:Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: Research support; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research support, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research support, Speakers Bureau; Incyte: 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, Other: Research support, Research Funding, Speakers Bureau. Gil:Jazz Pharmaceuticals: Honoraria; Gilead: Honoraria; Daiichi-Sankyo: Honoraria; Novartis: Honoraria, Research Funding; Pfizer: Honoraria; Abbvie: Honoraria. Perez De Oteyza:Celgene: Speakers Bureau. Rowe:BioSight: Consultancy. Wolach:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaker; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaker. Sun:MacroGenics, Inc.: Employment, Equity Ownership. Baughman:MacroGenics, Inc.: Employment, Equity Ownership. McNulty:MacroGenics, Inc.: Employment, Equity Ownership. Bonvini:MacroGenics, Inc.: Employment, Equity Ownership. Wigginton:Western Oncolytics: Other: clinical advisory board; MacroGenics, Inc.: Employment, Equity Ownership. Davidson-Moncada:MacroGenics, Inc.: Employment, Equity Ownership.

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