CC-122 Dosing on a Novel Intermittent Schedule Mitigates Neutropenia and Maintains Clinical Activity in Subjects with Relapsed or Refractory Diffuse Large B Cell Lymphoma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1494-1494 ◽  
Author(s):  
Cecilia Carpio ◽  
Loïc Ysebaert ◽  
Raúl Cordoba ◽  
Armando Santoro ◽  
José Antonio López-Martín ◽  
...  
Keyword(s):  
T Cells ◽  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
B Cell Lymphoma ◽  
Clinical Activity ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Grade 3

Abstract Background: CC-122, a first in class PPM™ pleiotropic pathway modifier, has anti-tumor activity against B cell lymphomas. The molecular target of CC-122 is cereblon (CRBN) and CC-122 promotes ubiquitination of lymphoid transcription factor Aiolos in a CRBN-dependent manner, leading to its degradation in Diffuse Large B Cell Lymphoma (DLBCL) tumor tissue and immune cells. CC-122 also depletes Ikaros, which is expressed in immature stages of myeloid differentiation and regulates early neutrophil differentiation (Blood 101:2219 2003). Following establishment of CC-122 3mg daily (QD) as the maximum tolerated dose (MTD) on a continuous schedule (Blood 122:2905 2013), subjects with advanced lymphoma, myeloma, and select solid tumors were enrolled in parallel expansion. In DLBCL subjects, CC-122 treatment demonstrated promising clinical efficacy, however, dose reductions due to neutropenia were frequent with the QD schedule (Blood 124:3500 2014). Therefore, a second cohort of DLBCL subjects was enrolled to evaluate the tolerability and clinical activity of intermittent schedules. Methods: Subjects with relapsed/refractory DLBCL were enrolled in parallel dose escalation of CC-122 given orally at 4mg or 5mg on two intermittent schedules. CC-122 given 21/28 days was tested based on lenalidomide experience. In order to model a second schedule, human bone marrow CD34+ cells were cultured for two weeks in SCF, Flt3L and G-CSF for expansion towards granulocytic lineage followed by 6 days with media plus G-CSF for neutrophil maturation.CC-122 0.5 uM was added continuously or on a 5 out of 7 day (5/7d) schedule. Myeloid maturation stages were measured 14 days later by CD34, CD33 and CD11b flow cytometry. Continuous exposure to CC-122 led to reversible myeloid maturation arrest and 90% decreased mature neutrophils compared to vehicle, whereas, CC-122 exposure for 5/7d resulted in only 50% decreased mature neutrophils. Based on this rationale, CC-122 given 5/7d was selected as the second intermittent schedule tested in DLBCL. Results: As of June 25, 2015, 22 subjects with relapsed/refractory DLBCL were enrolled in the 2nd cohort; all were evaluable for safety, 16 were efficacy evaluable (EE) as of the cutoff date. The median age was 60 years and 54% were male. The median time since diagnosis was 14 months and all subjects were ECOG 0-1. For subjects treated with CC-122 4mg 21/28 days (N=3), there were no dose limiting toxicities (DLTs) in cycle 1, however, all subjects required dose reduction due to neutropenia and therefore this dose level was considered a non-tolerated dose (NTD). For subjects treated with CC-122 on a 5/7 days schedule, the NTD was at 5mg due to 2 DLTs in 2 of 5 subjects (grade 3 febrile neutropenia and grade 3 pneumonitis). CC-122 4mg was the MTD on 5/7d and was selected for ongoing expansion in up to 50 subjects (N=14 as of cutoff date). There were no DLTs in 12 DLT-evaluable subjects. Median relative dose intensity achieved for 4mg 5/7d vs 3mg QD was 99% vs 79%. The most common (≥ 10%) related adverse events (AEs) were neutropenia (36%), constipation (29%), asthenia (21%) and grade 3/4 related AEs were neutropenia (36%) and lipase elevation (14%). In addition, drug-related serious AEs included pneumonia, neck pain, and respiratory failure. AEs were an uncommon cause of discontinuation (7%, n=14). Response rates for the EE DLBCL subjects treated at 5mg 5/7d (N=3), 4mg 5/7d (N=10), and 3mg QD (N=22) was 67% (2 PR), 30% (1CR, 2 PR) and 23% (1CR, 4PR), respectively. Aiolos protein levels in peripheral T cells was measured by flow cytometry pre (baseline) and 5 hours post dosing on C1D1, C1D10 and C1D22. The median % change Aiolos levels at each of these visits were -47, -28 and -52%, respectively, indicating that Aiolos degradation occurs throughout the cycle. In addition, the median increase from baseline in cytotoxic memory T cells and helper memory T cells at cycle 1 day 22 in peripheral blood samples was 580% and 76%, respectively. Conclusion: In an in vitro myeloid differentiation assay, myeloid maturation arrest by CC-122, possibly due to Ikaros degradation, can be partially bypassed with a 2 day drug holiday. From a clinical standpoint, exploration of intermittent dosing confirmed that 5/7d schedule mitigates neutropenia-related dose reductions and improves CC-122 clinical activity in relapse/refractory DLBCL patients. Of note, the immunomodulatory effects of CC-122 are maintained on the 5/7d schedule. Disclosures Carpio: Celgene: Research Funding. Off Label Use: CC-122 is a first in class PPM(TM) pleiotropic pathway modifier with anti-tumor activity against B cell lymphomas.. Ysebaert:Celgene: Research Funding. Cordoba:Celgene: Research Funding. Santoro:Celgene: Research Funding. López-Martín:Celgene: Research Funding. Sancho:Celgene: Research Funding. Panizo:Celgene: Research Funding; Roche: Speakers Bureau; Janssen: Speakers Bureau; Takeda: Speakers Bureau. Gharibo:Celgene: Research Funding. Rasco:Asana BioSciences, LLC: Research Funding; Celgene: Research Funding. Stoppa:Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Damian:Celgene: Research Funding. Wei:Celgene: Employment, Equity Ownership. Hagner:Celgene: Employment, Equity Ownership. Hege:Celgene Corporation: Employment, Equity Ownership. Carrancio:Celgene: Research Funding. Gandhi:Celgene: Employment, Equity Ownership. Pourdehnad:Celgene: Employment, Equity Ownership. Ribrag:Esai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmamar: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Phase II Study Of Anti-CD19 Antibody Drug Conjugate (SAR3419) In Combination With Rituximab: Clinical Activity and Safety In Patients With Relapsed/Refractory Diffuse Large B-Cell Lymphoma (NCT01470456)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4395-4395 ◽  
Author(s):  
Bertrand Coiffier ◽  
Catherine Thieblemont ◽  
Sophie de Guibert ◽  
Jehan Dupuis ◽  
Vincent Ribrag ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Clinical Activity ◽  
Advisory Committees ◽  
Large B Cell Lymphoma ◽  
Duration Of Response ◽  
Grade 3

Abstract Background SAR3419 is a humanized anti-CD19 antibody conjugated to maytansin DM4, a potent cytotoxic agent. SAR3419 targets CD19, an antigen expressed in the majority of B cell non-Hodgkin lymphomas (NHL). The recommended dose for single agent SAR3419 was previously determined to be 55 mg/m2 administered IV every week for 4 weeks, then bi-weekly. In phase I, clinical activity was shown mainly in patients with follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). (Trial funded by Sanofi). Methods Patients (pts) with a CD20+ and CD19+ DLBCL relapsing or refractory (R/R) after at least 1 standard treatment including rituximab and not candidate for or who already underwent transplantation, were eligible. Refractory disease was defined as unresponsive to or progressing within 6 months of regimen completion. Fresh (or recent formalin-fixed, paraffin-embedded) biopsy was required before SAR3419 start. Pts received 375 mg/m2 of rituximab (R) IV and 55 mg/m² of SAR3419 on day 1, 8, 15, 22 (35-day cycle 1), followed by bi-weekly R and SAR3419 at the same doses for 2 additional 28-day cycles, provided there was no disease progression or other study discontinuation criteria met. The primary objective was the overall response rate (ORR) following Cheson 2007 criteria, with the first tumor assessment being done 42 days after the last study treatment administration. Secondary objectives were: safety, pharmacokinetics (PK), duration of response (DOR), progression free survival (PFS), overall survival (OS) and correlation of the antitumor and biological activity of the combination with tumor biomarker status. Results Fifty-three pts were enrolled, 52 treated. Median age was 66.5 years (range 38-85), 50% were male; 23%, 33% and 40% of patients had received 1, 2 or ≥3 prior chemo/immunotherapy regimens for DLBCL, respectively. Of the enrolled patients, 3.8% had received no prior regimen for DLBCL and therefore were excluded from primary analysis for efficacy. Seventy-three percent had stage III/IV disease, 59% had elevated lactate dehydrogenase (LDH), and 63% had bulky disease. Sixty percent were refractory to first regimen (primary refractory), 16% were refractory to last regimen and 24% were relapsed pts. The ORR in the per-protocol population (n=45) was 31.1% (80% confidence interval (CI): 22.0% to 41.6%). Among the 14 responders, 5 had progressed at the time of analysis, with duration of response beyond 6 months for 3 of them. The ORR was 58.3% (80% CI: 36.2% to 78.1%) for patients with relapsed DLBCL (n=12), 42.9% (80% CI: 17.0% to 72.1%) for pts refractory to last regimen (n=7) and 15.4% (80% CI: 6.9% to 28.4%) for primary refractory pts (n=26). Overall survival and PFS data are not yet mature. Biomarkers and PK data will be presented at the meeting. The most common (≥10%) all grades non-hematologic treatment-emergent adverse events (TEAEs) were asthenia (25.0%), nausea (21.2%), cough (19.2%), diarrhea (17.3%), weight decrease (17.3%), vomiting (15.4%), dyspnea (15.4%), abdominal pain (13.5%), back pain (13.5%), pyrexia (13.5%) and constipation (11.5%). Related grade 3-4 TEAEs were: 1 syncope, 1 bronchospasm, 2 neutropenia and 1 anemia. No TEAEs led to treatment discontinuation, no grade 3-4 peripheral neuropathy or grade 3-4 ocular events were observed. Two pts experienced grade 2 keratitis, both rapidly recovered with local treatment. Hematological toxicity was moderate, with grade 3-4 neutropenia and thrombocytopenia in 15.7% and 9.8% pts, respectively. No complications related to neutropenia were reported. Grade 3 transaminase increase was observed in 1 patient. Conclusions The combination of SAR3419 plus R showed moderate ORR in R/R DLBCL; however the study population was of poor prognosis (60% refractory to first line therapy). In the relapsed DLBCL patients a higher ORR was observed. SAR3419 plus R presented with a favorable safety profile. Further investigations on biomarker expression are ongoing to identify a sub-group of pts who could have better benefited from this combination. Disclosures: Coiffier: Sanofi: Membership on an entity’s Board of Directors or advisory committees. Off Label Use: Phase II of SAR3419. Ribrag:Johnson & Johnson: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Takeda: Membership on an entity’s Board of Directors or advisory committees; Servier: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Cartron:LFB: Honoraria; GSK: Honoraria; Roche: Consultancy, Honoraria, Speakers Bureau. Casasnovas:Roche: Consultancy, Honoraria, Research Funding. Hatteville:Sanofi: Employment. Zilocchi:Sanofi: Employment. Oprea:Sanofi: Employment. Tilly:Amgen: Research Funding; Janssen: Honoraria; Pfizer: Honoraria; Takeda: Membership on an entity’s Board of Directors or advisory committees; Roche: Honoraria; Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding.

scholarly journals First-in-Human, Phase 1/2 Trial to Assess the Safety and Clinical Activity of Subcutaneous GEN3013 (DuoBody®-CD3×CD20) in B-Cell Non-Hodgkin Lymphomas

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 758-758 ◽  
Author(s):  
Pieternella Lugtenburg ◽  
Rogier Mous ◽  
Michael Roost Clausen ◽  
Martine E.D. Chamuleau ◽  
Peter Johnson ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
Clinical Activity ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Introduction: CD20-specific monoclonal antibodies (mAbs) have demonstrated efficacy in the treatment of B-cell non-Hodgkin lymphomas (B-NHL); however, a significant proportion of patients (pts) present with refractory disease or will experience relapse. GEN3013 (DuoBody®-CD3×CD20) is the first subcutaneously administered IgG1 bispecific antibody (bsAb) that targets the T-cell surface antigen CD3 and the B-cell surface antigen CD20, triggering T-cell-mediated killing of B cells. In vitro, GEN3013 efficiently activates and induces cytotoxic activity of CD4+ and CD8+ T cells in the presence of B cells (Hiemstra et al. Blood 2018), and results in long-lasting depletion of B cells in cynomolgus monkeys. Subcutaneous (SC) GEN3013 in cynomolgus monkeys resulted in lower plasma cytokine levels, and similar bioavailability and B-cell depletion, compared with intravenous administration. GEN3013 has higher potency in vitro than most other CD3×CD20 bsAbs in clinical development (Hiemstra et al. HemaSphere 2019). SC GEN3013 in pts with B-NHL is being evaluated in a first-in-human, Phase 1/2 trial (NCT03625037), which comprises a dose-escalation part and a dose-expansion part. Here we report preliminary dose-escalation data. Methods: Pts with CD20+ B-NHL with relapsed, progressive, or refractory disease following anti-CD20 mAb treatment, and ECOG PS 0-2 were included. During dose escalation, pts received SC GEN3013 flat dose in 28-day cycles (q1w: cycle 1-2; q2w: cycle 3-6; q4w thereafter) until disease progression or unacceptable toxicity. Risk of cytokine release syndrome (CRS) was mitigated with the use of a priming dose and premedication with corticosteroids, antihistamines, and antipyretics. Primary endpoints were adverse events (AEs) and dose-limiting toxicities (DLTs). Secondary endpoints included pharmacokinetics (PK), immunogenicity (anti-drug antibodies [ADA]), pharmacodynamics (PD) (cytokine measures; laboratory parameters), and anti-tumor activity (tumor size reduction; objective and best response). Results: At data cut-off (June 28, 2019), 18 pts were enrolled into the dose-escalation part of the trial, with safety data available for pts receiving doses starting at 4 µg. Most pts had diffuse large B-cell lymphoma (DLBCL; n=14) and were heavily pre-treated; 10 pts had received ≥3 prior lines of therapy (overall median [range]: 3 [1-11]). The median age was 58.5 years (range: 21-80), and 13 pts were male. At a median follow-up of 1.9 months, pts received a median of 5 doses (range: 1-14); treatment is ongoing in 6 pts. Twelve pts discontinued treatment due to progressive disease. Six pts died (2 during treatment, 4 during survival follow-up), all due to disease progression and unrelated to treatment. The most common (n≥5) treatment-emergent AEs were pyrexia (n=8), local injection-site reactions (n=7), diarrhea (n=5), fatigue (n=5), and increased aspartate aminotransferase (n=5). The most common Grade (G) 3/4 AEs were anemia (n=3) and neutropenia (n=3). Despite increasing GEN3013 doses, all CRS events were non-severe (initial observation: 3/8 pts, G1: n=1, G2: n=2; following modification of premedication plan [corticosteroids for 3 days]: 6/10 pts, G1: n=4, G2: n=2). Increases in peripheral cytokine (IL6, IL8, IL10, IFNγ, TNFα) concentrations after GEN3013 dosing correlated with clinical symptoms of CRS in most pts. No pts had tumor lysis syndrome or neurological symptoms. No DLTs were observed. GEN3013 PK profiles reflect SC dosing; Cmax occurred 2-4 days after dosing. No ADAs were detected. PD effects following GEN3013 dosing were observed at dose levels as low as 40 µg and included rapid, complete depletion of circulating B cells (if present after prior anti-CD20 therapy) and peripheral T-cell activation and expansion. The first evidence of clinical activity was observed at a dose level of 120 µg, with complete metabolic response observed in a pt with DLBCL. Conclusions: Subcutaneously administered GEN3013, a potent CD3×CD20 bsAb, shows good tolerability and early evidence of clinical activity at low dose levels in heavily pretreated pts with relapsed or refractory B-NHL. All CRS events were non-severe and did not lead to discontinuation. No DLTs were observed. Dose escalation is ongoing; updated data will be presented. Dose expansion will begin upon determining the recommended Phase 2 dose (RP2D) (NCT03625037). Disclosures Lugtenburg: Janssen Cilag: Honoraria; Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria; Servier: Consultancy, Honoraria, Research Funding; Genmab: Consultancy, Honoraria; BMS: Consultancy; Takeda: Consultancy, Honoraria, Research Funding. Mous:Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Sandoz: Honoraria; Roche: Honoraria; Abbvie: Honoraria; Takeda: Honoraria, Research Funding; Janssen Cilag: Consultancy, Honoraria; MSD: Honoraria; Gilead: Consultancy, Honoraria, Research Funding. Clausen:Abbvie: Other: Travel grant to attend ASH 2019. Johnson:Boehringer Ingelheim: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Honoraria; Epizyme: Honoraria, Research Funding; Incyte: Honoraria; Takeda: Honoraria; Genmab: Honoraria; Bristol-Myers Squibb: Honoraria; Kite: Honoraria; Novartis: Honoraria. Rule:Janssen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Astra-Zeneca: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Napp: Consultancy; Kite: Consultancy. Oliveri:Genmab: Employment, Equity Ownership. DeMarco:Genmab: Employment, Equity Ownership. Hiemstra:Genmab: Employment, Equity Ownership, Other: Warrants. Chen:Genmab: Employment. Azaryan:Genmab: Employment. Gupta:Genmab: Employment, Equity Ownership. Ahmadi:Genmab Inc: Employment, Other: stock and/or warrants. Hutchings:Incyte: Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Genmab: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Janssen: Research Funding; Pfizer: Research Funding.

Final Phase I Results of Perifosine In Combination with Lenalidomide and Dexamethasone In Patients with Relapsed or Refractory Multiple Myeloma (MM)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3064-3064
Author(s):  
Andrzej J Jakubowiak ◽  
Paul G Richardson ◽  
Todd M Zimmerman ◽  
Melissa Alsina ◽  
Jonathan L. Kaufman ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Clinical Activity ◽  
Final Phase ◽  
Employment Equity ◽  
Advisory Committees ◽  
Prior Therapy ◽  
Ortho Biotech ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 3064 Introduction: Perifosine (Peri) a novel, oral signal transduction modulator with multiple effects including inhibition of Akt and activation of JNK, has demonstrated clinical activity when combined with dexamethasone (Dex) in patients (pts) with relapsed/refractory MM (ASH 2007 #1164). Lenalidomide (Revlimid , Rev) a novel, oral immunomodulatory drug has activity against MM when combined with Dex. We previously reported encouraging safety data and observed clinical activity of the oral triplet combination (ASH 2008 # 3691). We now report the final phase I results of this study which aimed to determine the MTD and to evaluate activity of Peri + Rev + Dex, as an oral combination in pts with relapsed or refractory MM. Methods: Four cohorts ( 6 pts each) were planned, dosing Peri at 50 or 100mg (daily), Rev 15 or 25mg (d 1–21) and Dex 20mg (d 1–4, 9–12 and 17–20 for 4 cycles, then 20 mg d 1–4) in 28-d cycles. To limit dex-related toxicities, the protocol was amended to use weekly dex (40 mg), applying to cohorts 3, 4, and the MTD cohort. Toxicity was assessed using NCI CTCAE v3.0; DLT was defined as grade (G) 3 non-hematologic toxicity, G4 neutropenia for 5 d and/or neutropenic fever, or platelets <25,000/mm3 on >1 occasion despite transfusion. Response was assessed by modified EBMT criteria. Pts had to have received at least 1 prior therapy and no more than 4. Pts refractory to Rev/Dex were excluded. Results: 32 pts (17M/15F, median age 64 y, range 37 – 79) were enrolled; 6 pts in cohort 1 (Peri 50mg, Rev 15mg, Dex 20mg); 6 pts in cohort 2 (Peri 50mg, Rev 25mg, Dex 20mg); 8 pts in cohort 3 (Peri 100mg, Rev 15mg, Dex 40mg/wk); 6 pts in cohort 4 (Peri 100mg, Rev 25mg, Dex 40mg/wk) and 6 pts at MTD (Cohort 4). Median prior lines of treatment was 2 (range 1–4) with a median PS of 1. Relapsed (53%), Refractory to last therapy prior to study entry (47%). Prior therapy included dex (94%), thalidomide (75%), bortezomib (44%), and stem cell transplant (72%). Two pts (6%) were previously treated with Rev. 63% (15/24) of the prior thalidomide + dex (Thal/Dex) treated pts had progressed on a Thal/Dex regimen while 43% (6/14) of the prior bortezomib (Vel) treated pts had progressed on a prior Vel based regimen. Two pts did not complete one full cycle (non-compliance and adverse event not related to study drugs – both in cohort 3) and were not included in the efficacy analysis. 31/32 pts were evaluable for safety (non-compliant patient never took study drug and was excluded). The most common grade 1/2 events (any causality) included fatigue (48%), diarrhea (45%), upper respiratory infection (35%), nausea (32%) and hyperglycemia (32%). Grade 3/4 events > 10% included neutropenia (26%); hypophosphatemia (23%); thrombocytopenia (16%) and leucopenia (13%). There was one reported DLT in cohort 3 (Nausea). No grade 3/4 events of peripheral neuropathy or DVT were reported. Rev dose was reduced in 11 pts, Peri reduced in 9 pts and Dex reduced in 7 pts: 30 pts are evaluable for response, with best response as follows: Median progression-free survival (PFS) for all pts was 10.8 mos (CI: 4.6, 27.7) and 7 pts have not progressed. The median overall survival (OS) was 30.6 mos (CI: 16.7, NR) with 15/30 pts still alive. Of the 8 thalidomide naïve pts, 4 have progressed with a median projected PFS of 30 mos and all 8 pts remain alive (range 28 – 43 mos). Conclusions: Pts have tolerated Peri + Rev + Dex well with manageable toxicity, and with promising clinical activity demonstrated by an ORR (≥ PR) of 50%, an extended PFS and OS. Given that most pts were exposed to Thal/Dex with more than half refractory to a prior Thal/Dex regimen, the encouraging response rates and survival appear to suggest benefit with the addition of perifosine to Rev/Dex. This data thus warrants further study, including a potential randomized trial to confirm the activity of perifosine added to Rev/Dex. A randomized phase III trial of Peri/Vel/Dex vs. Vel/Dex is underway for previously Vel exposed MM patients. Disclosures: Jakubowiak: Millennium, Celgene, Bristol-Myers Squibb, Johnson & Johnson Ortho-Centocor: Honoraria; Millennium, Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Millennium, Celgene, Centocor-Ortho Biotech: Speakers Bureau. Off Label Use: Perifosine in combination with Lenalidomide and Dexamethasone. Richardson:Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees. Zimmerman:Millennium, Celgene: Speakers Bureau. Alsina:Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Ortho Biotech: Research Funding. Kaufman:Celgene, Millenium: Consultancy; Celgene, Merck: Research Funding. Sportelli:Keryx Biopharmaceuticals: Employment, Equity Ownership. Gardner:Keryx Biopharmaceuticals: Employment, Equity Ownership. Anderson:Celgene: Consultancy, Honoraria, Speakers Bureau; Millennium: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau.

A Phase 2 Multicenter Trial of KTE-C19 (anti-CD19 CAR T Cells) in Patients With Chemorefractory Primary Mediastinal B-Cell Lymphoma (PMBCL) and Transformed Follicular Lymphoma (TFL): Interim Results From ZUMA-1

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 998-998 ◽  
Author(s):  
Sattva S. Neelapu ◽  
Frederick L. Locke ◽  
Nancy L Bartlett ◽  
Tanya Siddiqi ◽  
Caron A. Jacobson ◽  
...  
Keyword(s):  
T Cells ◽  
B Cell ◽  
Board Of Directors ◽  
B Cell Lymphoma ◽  
Cell Transplant ◽  
Employment Equity ◽  
Advisory Committees ◽  
Car T Cells ◽  
Car T ◽  
Equity Ownership

Abstract Background: ZUMA-1 is a phase 1-2 multicenter, open-label study evaluating the safety and efficacy of KTE-C19 in patients with refractory aggressive B-cell non-Hodgkin lymphoma. In phase 1, KTE-C19 demonstrated ongoing complete remissions with a tolerable safety profile (Neelapu, ASCO 2016). The phase 2 portion of the study has 2 cohorts based on tumor type: diffuse large B-cell lymphoma (cohort 1) or PMBCL/TFL (cohort 2). Results from cohort 2 at the time of the first pre-specified interim analysis of ZUMA-1 are presented here. Methods: Patients received KTE-C19 at a target dose of 2 × 106 (minimum 1 × 106) anti-CD19 chimeric antigen receptor (CAR) T cells/kg after a low-dose conditioning chemotherapy regimen of cyclophosphamide (500 mg/m2) and fludarabine (30 mg/m2) daily for 3 days. The primary endpoint was overall remission rate per International Working Group criteria (Cheson, J Clin Oncol2007). Key secondary endpoints include duration of response, incidence of adverse events (AEs), levels of CAR T cells in the blood, and levels of serum cytokines. Key inclusion criteria include ≥ 18 years old, Eastern Cooperative Oncology Group (ECOG) performance status 0-1, and chemorefractory disease defined as progressive disease or stable disease as best response to last line of therapy, or disease progression ≤12 months after autologous stem cell transplant. Patients must have received prior anti-CD20 therapy and an anthracycline-containing regimen. Results: As of June 16, 2016, six patients in cohort 2 were treated with KTE-C19 and had at least 30 days of follow up. The median follow up time was 3.2 months. Fifty percent of patients had PMBCL and 50% had TFL. Median age was 55 years (range, 28-60), 67% were male, 67% ECOG performance status 0, and 50% were refractory to second or greater line of chemotherapy while 50% relapsed after autologous stem cell transplant. The objective response rate was 100%. All patients have ongoing complete remissions. Worst grades 3 and 4 treatment-emergent AEs occurred in 17% and 67% of patients, respectively. There were no grade 5 events. All grade 4 treatment-emergent AEs were cytopenias. KTE-C19-related worst grade 3 and 4 AEs occurred in 50% and 17% of patients, respectively. Patient incidence of any grade/grade 3/grade 4 CRS and neurotoxicity were 100%/0%/0% and 67%/33%/0%, respectively. All KTE-C19-related AEs have resolved. Biomarker endpoints will be presented. Conclusions: KTE-C19 demonstrated early promising activity in patients with refractory PMBCL and TFL. The predominant toxicities of CRS and neurotoxicity were generally reversible. Updated trial results from 11 patients at interim analysis 2 will be presented. Clinical trial: NCT02348216. This study is supported in part by funding from The Leukemia & Lymphoma Society (LLS) Therapy Acceleration Program® Disclosures Locke: Kite: Membership on an entity's Board of Directors or advisory committees. Bartlett:Gilead: Consultancy. Siddiqi:Pharmacyclics, LLC, an AbbVie Company: Speakers Bureau; Janssen: Speakers Bureau; Seattle Genetics: Speakers Bureau; Kite pharma: Other: Funded travel, 1 day registration, and 1 night hotel stay for EHA2016 so I could present trial data there. . Jacobson:Kite: Membership on an entity's Board of Directors or advisory committees. Westin:ProNAi: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Chugai: Membership on an entity's Board of Directors or advisory committees. Chavez:Janssen: Speakers Bureau. LaCasce:Seattle Genetics: Consultancy; Seattle Genetics: Consultancy; Forty Seven: Consultancy; Forty Seven: Consultancy. Bot:Kite Pharma: Employment, Equity Ownership. Rossi:Kite Pharma: Employment, Equity Ownership. Jiang:Kite Pharma: Employment, Equity Ownership. Aycock:Kite Pharma: Employment, Equity Ownership. Elias:Kite: Employment, Equity Ownership. Wiezorek:Kite Pharma: Employment, Equity Ownership. Go:Kite Pharma: Employment, Equity Ownership.

scholarly journals Phase 2 Study of Zanubrutinib (BGB-3111) in Patients with Relapsed/Refractory Marginal Zone Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5256-5256 ◽  
Author(s):  
Stephen Opat ◽  
Robert Marcus ◽  
Craig A. Portell ◽  
William Reed ◽  
Chris Tankersley ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Marginal Zone ◽  
Marginal Zone Lymphoma ◽  
Phase 2 ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Grade 3

Background: Bruton tyrosine kinase (BTK) plays a critical role in B-cell receptor signaling, which mediates B-cell proliferation, migration, and adhesion. Inhibition of BTK has emerged as a strategy for targeting B-cell malignancies including marginal zone lymphoma (MZL). Zanubrutinib (BGB-3111) is an investigational, next-generation BTK inhibitor that was designed to maximize BTK occupancy and minimize off-target inhibition of TEC- and EGFR-family kinases. Increased specificity may minimize toxicities reported with ibrutinib potentially due to off-target inhibition such as diarrhea, thrombocytopenia, bleeding, atrial fibrillation, rash, and fatigue (Coutre et al. Blood Advances 2019). In non-clinical studies, zanubrutinib has been shown to be highly potent, selective, bioavailable, and irreversible, with potentially advantageous pharmacokinetic and pharmacodynamic properties. Complete and sustained BTK occupancy has been observed with zanubrutinib treatment in both peripheral blood mononuclear cells and in lymph nodes (Tam et al. Blood 2019). Based on drug-drug interaction studies and population PK analyses (internal data), zanubrutinib may be co-administered with strong or moderate CYP3A4 inhibitors at a reduced dose, proton pump inhibitors, vitamin K antagonists, as well as direct oral anticoagulants. Zanubrutinib does not prolong the QT interval. Pooled clinical data from 6 zanubrutinib monotherapy trials including 682 patients with either non-Hodgkin lymphoma, Waldenström macroglobulinemia, or chronic lymphocytic leukemia suggests that zanubrutinib has been generally well tolerated amongst patients with B-cell malignancies (Tam et al. EHA 2019). This data further showed that some toxicities often associated with BTK inhibitors were infrequent with zanubrutinib, including 1.9% atrial fibrillation/flutter (0.6% grade ≥3), 2.5% major hemorrhage (2.1% grade ≥3), 10.9% fatigue (0.7% grade ≥3), 18.0% rash (0.1% grade ≥3), 18.3% thrombocytopenia (6.6% grade ≥3), and 19.4% diarrhea (0.9% grade ≥3). Early clinical data from a phase 1 study demonstrated responses in 7 of 9 patients with relapsed/refractory (R/R) MZL treated with zanubrutinib (Tam et al. ASH 2017); the remaining 2 patients had stable disease indicating an encouraging rate of overall disease control. Study Design and Methods: This ongoing global phase 2, single-arm, open-label study (MAGNOLIA; NCT03846427) is examining zanubrutinib monotherapy in patients with R/R MZL who have received 1 or more prior lines of systemic therapy (Figure). Eligible patients must have histologically confirmed diagnosis of MZL including splenic, nodal, and extranodal subtypes, have received prior anti-CD20 antibody therapy, and have measurable disease. Patients must have documented clinical need for therapy as well as adequate marrow and organ function. Patients are treated with oral zanubrutinib at 160 mg twice daily until progressive disease, unacceptable toxicity, or withdrawal of consent. The primary efficacy endpoint is ORR according to the Lugano Classification (Cheson et al. J Clin Oncol. 2014) measured by computed tomography and bone marrow assessment data as determined by an independent review committee (IRC). A 2-sided Clopper-Pearson 95% CI for ORR will be calculated. Key secondary endpoints include ORR by investigator assessment, time to and duration of response, time to treatment discontinuation, progression-free survival (all determined by IRC and investigator assessments), overall survival, safety, and patient-reported outcomes. All patients are tested for the MYD88 mutation at study entry. Recruitment is ongoing. Disclosures Opat: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Amgen: Research Funding; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Epizyme: Research Funding; CSL: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Research Funding; Novartis: Consultancy. Marcus:Gilead: Consultancy; Roche: Other: Travel, Accommodations, Expenses, Speakers Bureau; Takeda: Other: Travel, Accommodations, Expenses; Roche-Genentech: Honoraria. Portell:Xencor: Research Funding; Roche/Genentech: Research Funding; Infinity: Research Funding; TG Therapeutics: Research Funding; Acerta/AstraZeneca: Research Funding; Kite: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Bayer: Consultancy; Amgen: Consultancy; Genentech: Consultancy, Research Funding; Janssen: Consultancy; AbbVie: Research Funding; Pharmacyclics: Consultancy. Reed:BeiGene: Employment, Equity Ownership, Other: Travel, Accommodations, Expenses. Tankersley:BeiGene: Employment, Equity Ownership. Huang:BeiGene: Employment, Equity Ownership. Trotman:Pharmacyclics: Research Funding; Roche: Research Funding; BeiGene: Research Funding; Janssen: Research Funding; Celgene: Research Funding. OffLabel Disclosure: Zanubrutinib is an investigational agent and has not yet been approved in the US

scholarly journals Preliminary Results of a Phase 1b Dose Escalation and Dose Expansion Study of GS-4059 in Combination with Idelalisib in Subjects with B-Cell Malignancies

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2961-2961 ◽  
Author(s):  
Gilles A. Salles ◽  
Franck Morschhauser ◽  
Bruce Cheson ◽  
Simon A. Rule ◽  
Christopher Fegan ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Employment Equity ◽  
Advisory Committees ◽  
Phase 1B ◽  
Equity Ownership ◽  
Grade 3

Abstract Introduction: Inhibitors of signaling downstream of the B-cell receptor have a demonstrated clinical benefit in a number of lymphoid malignancies but generally require chronic therapy with the potential for single mutations to lead to resistance. GS-4059 (ONO-4059) is a Bruton's tyrosine kinase (BTK) inhibitor. GS-4059 is safe and tolerable as a single agent at doses up to 480 mg in non-Hodgkin lymphoma and up to 600 mg in chronic lymphocytic leukemia (CLL). Idelalisib, a phosphatidylinositol-3-kinase delta (PI3Kd) inhibitor, is approved for the treatment of CLL. Single-agent therapy leads to durable responses, but with limited depth of response; treatment with a combination of GS-4059 and idelalisib has the potential to lead to deeper and more durable responses at lower doses of individual agents than needed as monotherapy. Methods:This ongoing, phase 1b study (NCT02457598) is evaluating the safety and tolerability of GS-4059 in combination with idelalisib. Patients with previously treated CLL, FL, small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), Waldenstrom's macroglobulinemia (WM), or non-germinal-center B-cell type (non-GCB) diffuse large B-cell lymphoma (DLBCL) and no prior exposure to BTK or PI3Kd inhibitors eligible for enrollment. Patients are enrolled using a 3+3 dose escalation design with a fixed dose of idelalisib (50 mg BID) and increasing doses of GS-4059. Optional dose expansion cohorts of up to 30 patients can be enrolled to generate disease-specific data. Patients were observed for a 28-day period to identify dose-limiting toxicities (DLTs). Efficacy evaluation was performed at 6-week intervals for DLBCL, 24-week intervals for CLL, and 12-week intervals for all other indications. Results: As of June 1, 2016, 20 patients have enrolled; the median age was 64 (37-79) years and 65% were men. The disease subtypes enrolled were CLL (n = 8), FL (5), MZL (2), SLL (2), and 1 each with DLBCL, MCL, and WM. The median number of prior therapies is 2.5 (range 1-4). The median duration of treatment is 113 days (range 29-310) with 17 patients still on-treatment. Three patients discontinued all study treatment due to disease progression (FL, MZL, DLBCL). There has been 1 death on study following progressive disease. Two DLTs of neutropenia were observed at dose level 2B (GS-4059 20 mg BID/idelalisib 50 mg BID), prompting the decision to discontinue the evaluation of twice-daily administration of GS-4059 when combined with idelalisib. The maximum tolerated dose (MTD) was not reached in Arm A of the study (Table 1). Of the 20 patients enrolled, 95% reported a treatment-emergent AE (TEAE), of which 55.0% were ≥grade 3. The only ≥grade 3 TEAE that was present in more than 1 patient was neutropenia. The most common TEAEs are listed in Table 2. Grade 3 liver laboratory test abnormalities were observed in 1 patient after approximately 5 months of treatment; a liver biopsy revealed a lymphocytic infiltrate consistent with CLL. Dose interruption due to an AE was reported in 45% of patients. Aside from 2 patients who discontinued idelalisib due to neutropenia and restarted therapy on GS-4059 alone, all patients successfully re-initiated therapy with both agents after treatment interruption. Nine patients have been on study for ≥24 weeks with 7 patients evaluable for radiographic response; 3 patients have had a >50% decrease in lymphadenopathy (CLL, SLL, FL). Preliminary pharmacokinetic (PK) results indicate that idelalisib at the evaluated dose levels does not significantly alter the PK of GS-4059. Conclusion: Once-daily dosing of GS-4059 up to 80 mg in combination with idelalisib 50 mg BID was generally safe and well tolerated. Early results show efficacy at combination doses significantly below the MTD for either single agent. This data supports continued clinical evaluation of the combination of GS-4059 and idelalisib for the treatment of B-cell malignancies. Disclosures Salles: Mundipharma: Honoraria; Novartis: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Gilead: Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Morschhauser:Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Janssen: Honoraria; Servier: Consultancy, Honoraria. Cheson:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Research Funding. Fegan:AbbVie: Honoraria; Roche: Honoraria; Gilead Sciences: Honoraria. Nelson:Gilead Sciences: Employment, Equity Ownership. Yang:Gilead Sciences: Employment, Equity Ownership. Mitra:Gilead Sciences: Employment, Equity Ownership. Starodub:Bayer: Consultancy; BMS: Speakers Bureau; Sandoz: Consultancy. Dyer:Roche: Consultancy, Speakers Bureau; ONO Pharmaceuticals: Research Funding; Gilead Sciences: Consultancy, Other: Travel funding, Research Funding, Speakers Bureau.

scholarly journals Data from the First CD20-Targeted Immunotoxin, MT-3724, in a Phase I/Ib Study in Relapsed/Refractory (R/R) Non-Hodgkin's B-Cell Lymphoma (NHL)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4200-4200 ◽  
Author(s):  
Paul A Hamlin ◽  
Michelle A. Fanale ◽  
Steven I. Park ◽  
David J. Valacer ◽  
Jack Higgins ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
B Cell Lymphoma ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Cd20 Antibodies

Abstract Background Novel mechanisms of action (MOA) are needed for the treatment of NHL. Because of the ubiquity and persistence of CD20 expression in B-cell malignancies, there is strong rationale to develop novel MOAs targeting CD20. However, CD20's non-internalizing nature has impeded the development of novel MOAs against this target.. MT-3724 is a recombinant fusion protein consisting of a CD20 binding variable fragment (scFv) fused to the ribosomal inhibitory protein Shiga-like toxin-I A1 subunit (SLT-I A1). Upon scFv binding to surface CD20, SLT-I A1 forces MT-3724 internalization and irreversibly inactivates cell ribosomes triggering cell death. MT-3724 has been shown to specifically bind and kill CD20+ malignant human B-cells in vitro and in in vivo animal models. Data from the first eighteen subjects evaluable for efficacy in the on-going Phase I/Ib monotherapy dose-escalation study of MT-3724 are presented. Methods MT-3724 is being tested in a first-in-human, open label, ascending dose study (3 + 3 design) in cohorts of 5, 10, 20, 50, 100, and 75 mcg/kg/dose. Eligible subjects who previously responded to a CD20 MAb containing therapy followed by relapse/recurrence of NHL receive 6 infusions over 2 hours in the first 12 days of a 28 day cycle (first cycle). With continued safety, tolerability and lack of tumor progression, subjects may receive 4 additional 6-dose cycles (21 days) with tumor assessments after cycles 2, 4 and 5. Dose escalation is based on < 33% dose limiting toxicities (DLTs) observed during the first 28 day cycle. Results To date, 18 R/R NHL subjects (mean number of prior therapies >4) have enrolled and completed at least one cycle in either the 5, 10, 20, 50, 100, or 75 mcg/kg/dose cohort. Two DLTs were identified in the 100 mcg/kg cohort considered possibly consistent with early signs/symptoms of capillary leak syndrome, a known side effect of immunotoxins. These adverse events (AEs) were non-life threatening and reversible upon drug withdrawal. The most common non-DLT AEs have been reversible hypoproteinemia (≤ Grade 2) with or without transient peripheral edema (≤ Grade 2). A summary of AEs and pharmacodynamic results will be presented. Anti-drug antibodies (ADA) have been observed with MT-3724 but the advent of ADA in subjects has not precluded deepening tumor responses. These data are consistent with the clinical experience of denileukin diftitox, the only approved toxin-based oncology therapeutic. Consistent signs of efficacy including responses were seen in subjects without recent exposure to CD20 antibodies (see table). Conversely, progression by cycle 2 was seen in all subjects who had recent CD20 antibody exposure. CD20 antibodies compete with MT-3724 for target binding and high tissue levels of CD20 antibodies likely inhibit MT-3724 activity. Conclusions Targeting CD20 with antibodies has substantially improved survival in NHL, but unmet need remains and there is strong rationale for agents with new MOAs. MT-3724 is the first CD20 targeted immunotoxin to enter clinic trials. Encouraging clinical activity has been seen; safety, efficacy, PK, and ADA data will be presented. Ribosome inhibition represents a novel mechanism of action for the treatment of R/R NHL and continued development of MT-3724 is warranted. *both Drs. Hamlin and Fanale contributed equally to this work Table Table. Disclosures Hamlin: Molecular Templates: Research Funding; Novartis: Research Funding; Xencor: Membership on an entity's Board of Directors or advisory committees; Portola: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding. Fanale:molecular templates: Research Funding. Valacer:Molecular Templates: Employment, Equity Ownership. Higgins:Molecular Templates: Employment, Equity Ownership. Younes:Molecular Templates: Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Interim Results from the First-in-Human Clinical Trial of Adct-402 (Loncastuximab Tesirine), a Novel Pyrrolobenzodiazepine-Based Antibody Drug Conjugate, in Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 398-398 ◽  
Author(s):  
John Radford ◽  
Brad S. Kahl ◽  
Mehdi Hamadani ◽  
Carmelo Carlo-Stella ◽  
Paolo Caimi ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
B Cell Lymphoma ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Abstract Introduction: Diffuse large B-cell lymphoma (DLBCL) represents 33% of the non-Hodgkin lymphomas (NHL) and expresses CD19, a classic B-cell marker found on B lymphocytes. ADCT-402 (loncastuximab tesirine; Lonca-T) is an antibody drug conjugate comprising a humanized antibody directed against human CD19 conjugated to a pyrrolobenzodiazepine dimer toxin. This first-in-human clinical study evaluated the safety and efficacy of Lonca-T in patients (pts) with relapsed/refractory (R/R) B-cell lineage NHL. Here we present interim results in the subgroup of pts with DLBCL. Interim efficacy and safety of Lonca-T in pts with follicular lymphoma and mantle cell lymphoma are presented in a separate abstract. Methods: Pts ≥18 years of age with R/R DLBCL who have failed or are intolerant to established therapies, or have no other treatment options available, were enrolled in this Phase 1, multicenter, open-label, single-arm study, including dose-escalation and dose-expansion parts. The primary objectives are to evaluate the safety and tolerability of Lonca-T, and determine the recommended dose(s) to use for expansion cohorts. The secondary objectives are to evaluate the clinical activity (measured by overall response rate [ORR], duration of response [DoR], progression-free survival [PFS] and overall survival [OS]), pharmacokinetics, pharmacodynamics, and anti-drug antibody activity. Pts receive 1-hour intravenous infusions of Lonca-T every 3 weeks (1 cycle), with a 3+3 dose-escalation design for the dose-escalation part of the study. No intra-pt dose escalation is allowed. Results: As of June 20, 2018, 183 pts had been enrolled on the study, including 137 with DLBCL (79 male, 58 female). Pts with DLBCL had a median age of 63 years [range 20-86], and had received a median of 3 previous therapies (range 1-10; Table). Pts received doses of Lonca-T ranging from 15 to 200 µg/kg (median cycles: 2 [range 1-13]). Treatment-emergent adverse events (TEAEs) were reported in 136/137 (99.3%) pts, and grade ≥3 TEAEs in 100/137 (73.0%) pts. The most common all-grade TEAEs (≥20% pts), regardless of relationship to study treatment, were fatigue (57 [41.6%]), nausea (44 [32.1%], peripheral edema (44 [32.1%]), anemia (39 [28.5%]), rash (35 [25.5%]), gamma-glutamyltransferase (GGT) increased (33 [24.1%]), constipation (30 [21.9%]), dyspnea (29 [21.2%]), and thrombocytopenia (28 [20.4%]). The most common grade ≥3 TEAEs (>10% pts) were GGT increased (21 [15.3%]), neutropenia (20 [14.6%]), neutrophil count decreased (19 [13.9%]), anemia (15 [10.9]), thrombocytopenia (15 [10.9%]) and platelet count decreased (14 [10.2%]. Approximately 66% and 72% of pts in the 120 and 150 µg/kg groups, respectively, tolerated at least 2 cycles before any AE leading to dose reduction/delay occurred. The figure depicts tumor response data. Out of 132 evaluable pts with DLBCL, the ORR was 40.2% (53/132 pts), comprising 29/132 (22.0%) complete responses (CRs) and 24/132 (18.2%) partial responses (PRs). Median DoR was 4.17 months and PFS was 2.79 months after a median follow-up of 5.13 months. Median DoR was not reached in pts achieving a CR and was 2.76 months in pts with a PR. In pts with non-bulky disease, the ORR was 44.2% (50/113 pts); 28/113 (24.8%) pts attained a CR and 22/113 (19.5%) pts attained a PR. The majority of pts (122/132) received doses ≥120 µg/kg; in these pts, the ORR was 41.8% (51/122 pts), with 28/122 (23.0%) pts attaining a CR and 23/122 (18.9%) pts attaining a PR. Conclusions: In this Phase 1 study, Lonca-T has demonstrated encouraging and durable single-agent antitumor activity and manageable toxicity in pts with R/R DLBCL at doses ≥120 µg/kg. Updated safety, tolerability, and efficacy results will be presented at the meeting. Study sponsored by ADC Therapeutics. http://clinicaltrials.gov/show/NCT02669017. Disclosures Radford: Pfizer: Research Funding; ADC Therapeutics: Consultancy, Research Funding; BMS: Consultancy, Speakers Bureau; GlaxoSmithKline: Equity Ownership; Seattle Genetics: Consultancy, Speakers Bureau; Takeda: Consultancy, Research Funding, Speakers Bureau; AstraZeneca: Equity Ownership; Novartis: Consultancy, Speakers Bureau; Celgene: Research Funding. Kahl:Seattle Genetics: Consultancy; Genentech: Consultancy; ADC Therapeutics: Research Funding. Hamadani:Sanofi Genzyme: Research Funding, Speakers Bureau; Takeda: Research Funding; Cellerant: Consultancy; Ostuka: Research Funding; MedImmune: Consultancy, Research Funding; ADC Therapeutics: Research Funding; Janssen: Consultancy; Celgene Corporation: Consultancy; Merck: Research Funding. Carlo-Stella:Boehringher Ingelheim Italia: Consultancy; Bristol-Myers Squibb: Speakers Bureau; Sanofi: Consultancy; MSD Italia: Speakers Bureau; Rhizen Pharmaceuticals: Research Funding; Genenta Science: Speakers Bureau; Janssen: Speakers Bureau; AstraZeneca: Speakers Bureau; Amgen: Speakers Bureau; ADC Therapeutics: Research Funding, Speakers Bureau. Caimi:Genentech: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Celgene: Speakers Bureau; Kite Pharma: Membership on an entity's Board of Directors or advisory committees. Ardeshna:Roche: Membership on an entity's Board of Directors or advisory committees, Other: Conference expenses, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: 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. Feingold:ADC Therapeutics: Employment, Equity Ownership. He:ADC Therapeutics: Employment, Equity Ownership. Reid:AbbVie: Research Funding; Millenium Pharmaceuticals: Research Funding; ADC Therapeutics: Research Funding. Solh:ADC Therapeutics: Research Funding; Celgene: Speakers Bureau; Amgen: Speakers Bureau. Chung:ADC Therapeutics: Research Funding. Heffner:Pharmacyclics: Research Funding; ADC Therapeutics: Research Funding; Kite Pharma: Research Funding; Genentech: Research Funding. Ungar:ADC Therapeutics: Employment, Equity Ownership. O'Connor:ADC Therapeutics: Research Funding; Seattle Genetics: Research Funding; Celgene: Research Funding.

scholarly journals 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 ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4196-4196 ◽  
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.

scholarly journals A Phase I Trial of Janus Kinase (JAK) Inhibition with INCB039110 in Acute Graft-Versus-Host Disease (aGVHD)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 390-390 ◽  
Author(s):  
Mark A. Schroeder ◽  
H. Jean Khoury ◽  
Madan Jagasia ◽  
Haris Ali ◽  
Gary J. Schiller ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Janus Kinase ◽  
Cell Transplant ◽  
Employment Equity ◽  
Advisory Committees ◽  
Daily Dose ◽  
Equity Ownership ◽  
Grade 3 ◽  
Steroid Refractory

Abstract Background: Corticosteroids are considered standard first-line systemic therapy for patients with aGVHD, but this approach is effective in only approximately half of all cases. For patients who progress or do not respond to corticosteroids, no specific agent has been identified as standard, and regimens are typically selected based on investigator experience and patient co-morbidities. In preclinical models, JAK inhibition has been shown to impair production of cytokines as well as the differentiation and trafficking of T cells implicated in the pathogenesis of aGVHD. Retrospective studies have suggested that JAK1/JAK2 inhibition with ruxolitinib treatment provides clinical benefit in patients with steroid-refractory GVHD (Zeiser et al, Leukemia 2015;29:2062-2068). Herein, we report preliminary safety results from a prospective randomized, parallel-cohort, open-label phase 1 trial evaluating the potent and selective JAK 1 inhibitor INCB039110 in patients with aGVHD. Methods: Male or female patients 18 years or older who underwent their first allo-hematopoietic stem cell transplant (HSCT) from any donor source and developed grades IIB-IVD aGVHD were eligible for the study. Patients were randomized 1:1 to either a 200 or 300 mg oral daily dose of INCB039110 in combination with corticosteroids, and were stratified based on prior treatment status (treatment-naive [TN] versus steroid-refractory [SR]). The primary endpoint of the study was safety and tolerability; secondary endpoints included overall response rate at Days 14, 28, 56, and 100, non-relapse mortality, and pharmacokinetic (PK) evaluations. Patients were assessed through Day 28 for dose-limiting toxicities (DLTs) and response. A Bayesian approach was used for continuous monitoring of DLTs from Days 1-28. Treatment continued until GVHD progression, unacceptable toxicity, or withdrawal from the study. Acute GVHD was graded according to MN-CIBMTR criteria; adverse events (AEs) were graded according to NCICTCAE v 4.03. Results: Between January and June 2016, 31 patients (TN, n=14; SR, n= 17) were randomized. As of July 25, 2016, data were available from 30 patients who received an oral daily dose of 200 mg (n=14) or 300 mg (n=16) INCB039110 in combination with 2 mg/kg methylprednisolone (or equivalent dose of prednisone). The median durations of treatment were 60.8 days and 56.5 days for patients receiving a daily dose of 200 mg and 300 mg INCB039110, respectively. One DLT of Grade 3 thrombocytopenia was reported. The most frequently reported AEs included thrombocytopenia/platelet count decrease (26.7%), diarrhea (23.3%), peripheral edema (20%), fatigue (16.7%), and hyperglycemia (16.7%). Grade 3 or 4 AEs occurred in 77% of patients and with similar frequency across dose groups and included cytomegalovirus infections (n=3), gastrointestinal hemorrhage (n=3), and sepsis (n=3). Five patients had AEs leading to a fatal outcome, including multi-organ failure (n=2), sepsis (n=1), disease progression (n=1), and bibasilar atelectasis, cardiopulmonary arrest, and respiratory distress (n=1); none of the fatal events was attributed to INCB039110. Efficacy and PK evaluations are ongoing and will be updated at the time of presentation. Conclusion: The oral, selective JAK1 inhibitor INCB039110 can be given safely to steroid-naive or steroid-refractory aGVHD patients. The safety profile was generally consistent in both dose groups. Biomarker evaluation, PK, and cellular phenotyping studies are ongoing. The recommended phase 2 dose will be selected and reported based on PK studies and final safety data. Disclosures Schroeder: Incyte Corporation: Honoraria, Research Funding. Khoury:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Jagasia:Incyte Corporation: Research Funding; Therakos: Research Funding; Janssen: Research Funding. Ali:Incyte Corporation: Research Funding. Schiller:Incyte Corporation: Research Funding. Arbushites:Incyte Corporation: Employment, Equity Ownership. Delaite:Incyte Corporation: Employment, Equity Ownership. Yan:Incyte Corporation: Employment, Equity Ownership. Rhein:Incyte Corporation: Employment, Equity Ownership. Perales:Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Chen:Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding. DiPersio:Incyte Corporation: Research Funding.

Sign in / Sign up

Export Citation Format

Share Document