The PI3K Inhibitor GDC-0941 Synergizes with Standard of Care Therapies to Induce Growth Inhibition and Apoptosis of Multiple Myeloma Cells.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3788-3788
Author(s):  
Veerendra Munugalavadla ◽  
Leanne Berry ◽  
Changchun Du ◽  
Sanjeev Mariathasan ◽  
Dion Slaga ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Research Funding ◽  
Single Agent ◽  
Standard Of Care ◽  
Rational Approach ◽  
Current Standard ◽  
Employment Equity ◽  
Specific Flow ◽  
Equity Ownership

Abstract Abstract 3788 Poster Board III-724 Multiple myeloma (MM) is a malignancy characterized by clonal expansion and accumulation of long-lived plasma cells within the bone marrow. Phosphatidylinositol 3' kinase (PI3K) -mediated signaling is frequently dysregulated in cancer and controls fundamental cellular functions such as cell migration, growth, survival and development of drug resistance in many cancers, including MM, and therefore represents an attractive therapeutic target. Here, we demonstrate in vitro, that a potent and selective pan-isoform PI3Kinhibitor, GDC-0941, modulates the expected pharmacodynamic markers, inhibits cell-cycle progression and induces apoptosis; overcomes resistance to apoptosis in MM cells conferred by IGF-1 and IL-6; and is additive or synergistic with current standard of care drugs including dexamethasone, melphalan, lenolidamide and bortezomib. In cell lines we find sensitivity to GDC-0941 is positively correlated with pathway activation as determined by phospho-AKT-specific flow-cytometry and Western-blot analysis. Preliminary results indicate apoptosis of MM cells is correlated with increased expression of the proapoptotic BH3-only protein BIM; mechanisms of increased apoptosis in MM will be further explored and an update presented. We further extend these in vitro findings to show that GDC-0941 has activity as a single agent in vivo and combines well with standard of care agents in several murine xenograft models to delay tumor progression and prolong survival. Our results suggest that GDC-0941 may combine well with existing therapies, providing a framework for the clinical use of this agent, and a rational approach to improving the efficacy of myeloma treatment. Disclosures: Munugalavadla: Genentech: Employment, Patents & Royalties. Berry:Genentech: Employment, Patents & Royalties. Du:Genentech, Inc.: Employment, Equity Ownership. Mariathasan:Genentech: Employment, Patents & Royalties. Slaga:Genentech: Employment, Patents & Royalties. Sun:Genentech Inc.: Employment. Chesi:Genentech, Inc.: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Merck: Research Funding. Bergsagel:Genentech: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Merck: Research Funding. Ebens:Genentech, Inc.: Employment, Equity Ownership, Patents & Royalties.

EZH2 Inhibitors Are Broadly Efficacious in Multiple Myeloma As Single Agent and in Combination with Standard of Care Therapeutics

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5672-5672 ◽  
Author(s):  
Shilpi Arora ◽  
Kaylyn Williamson ◽  
Shruti Apte ◽  
Srividya Balachander ◽  
Jennifer Busby ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Lines ◽  
Single Agent ◽  
Standard Of Care ◽  
Tumor Growth Inhibition ◽  
Sequencing Data ◽  
Employment Equity ◽  
Chip Sequencing ◽  
Equity Ownership

Abstract Post-translational modifications of the histone proteins play a key role in regulating processes that require access to DNA. Specifically, methylation of lysine 27 on histone 3 (H3K27) is intimately linked with transcriptional repression. EZH2, a histone lysine methyl transferase is the catalytic component of the PRC2 complex, which catalyzes H3K27 methylation. EZH2 dysregulation has been observed in different malignancies and inhibition of its catalytic activity has emerged as a novel therapeutic approach to treat human cancers. Potent, selective and reversible EZH2 small molecule inhibitors are currently being tested in Ph. 1 clinical trials. We and others have reported EZH2 dependencies across non-Hodgkin Lymphoma subtypes in cancer cell lines, in xenograft mouse models and in lymphoma patients. We identified Multiple Myeloma as potential clinical application for EZH2 inhibitors. Treatment with EZH2 inhibitors such as CPI-360, CPI-169 and CPI-1205 cause apoptosis in multiple myeloma and plasmacytoma cell models and causes tumor growth inhibition in myeloma xenograft models at well tolerated doses. An EZH2-controlled transcriptional signature across various multiple myeloma was identified using integrated RNA-sequencing and ChIP-sequencing data. Combination studies testing EZH2 inhibitors with standard of care (SOC) agents across a panel of multiple myeloma cell lines showed synergistic responses with several of the SOC agents in vitro and in vivo. Disclosures Arora: Constellation Pharmaceuticals: Employment, Equity Ownership. Williamson:Constellation Pharmaceuticals: Employment, Equity Ownership. Apte:Constellation Pharmaceuticals: Employment, Equity Ownership. Balachander:Constellation Pharmaceuticals: Employment, Equity Ownership. Busby:Constellation Pharmaceuticals: Employment, Equity Ownership. Hatton:Constellation Pharmaceuticals: Employment, Equity Ownership. Bryant:Constellation Pharmaceuticals: Employment, Equity Ownership. Trojer:Constellation Pharmaceuticals: Employment, Equity Ownership.

A Phase I/II Trial of the KSP Inhibitor ARRY-520 In Relapsed/Refractory Multiple Myeloma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1959-1959 ◽  
Author(s):  
Jatin J Shah ◽  
Jeffrey A. Zonder ◽  
Adam Cohen ◽  
Donna Weber ◽  
Sheeba Thomas ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Dose Escalation ◽  
Research Funding ◽  
Phase 1 ◽  
Single Agent ◽  
Clinical Activity ◽  
Employment Equity ◽  
Heavily Pretreated ◽  
Equity Ownership ◽  
Ksp Inhibitor

Abstract Abstract 1959 Background: Kinesin Spindle Protein (KSP) is required for cell cycle progression through mitosis. Inhibition of KSP induces mitotic arrest and cell death. ARRY-520 is a potent, selective KSP inhibitor. Cancers such as multiple myeloma (MM) which depend on the short-lived survival protein MCL-1 are highly sensitive to treatment with ARRY-520. ARRY-520 shows potent activity in preclinical MM models, providing a strong rationale for its clinical investigation in this disease. Methods: This Phase 1 study was designed to evaluate the safety and pharmacokinetics (PK) of ARRY-520 administered intravenously (IV) on Day 1 and Day 2 q 2 weeks without/with granulocyte-colony stimulating factor (G-CSF). Patients (pts) with relapsed/refractory (RR) MM with 2 prior lines of therapy (including both bortezomib and an immunomodulatory agent, unless ineligible for or refusing to receive this therapy) were eligible. Cohorts of at least 3 pts were enrolled in a classical 3 + 3 dose escalation design. Pts were treated for 2 cycles (4 weeks) to evaluate safety prior to dose escalation. Results: Twenty five pts have been treated to date, with a median age of 60 years (range 44–79) and a median of 5 prior regimens (range 2–16). All pts received prior bortezomib or carfilzomib, 21 pts received prior lenalidomide, 17 pts prior thalidomide, and 18 pts had a prior stem cell transplant. Pts received ARRY-520 without G-CSF at 1 mg/m2/day (n = 3), and at 1.25 mg/m2/day (n = 7, 6 evaluable). A dose-limiting toxicity (DLT) of Grade 4 neutropenia was observed at 1.25 mg/m2/day, and this was considered the maximum tolerated dose (MTD) without G-CSF. As neutropenia was the DLT, dose escalation with prophylactic G-CSF support was initiated, at doses of 1.5 mg/m2/day (n = 7, 6 evaluable), 2.0 mg/m2/day (n = 6) and 2.25 mg/m2/day (n = 2) with G-CSF. Both the 2.0 mg/m2/day and 2.25 mg/m2/day dose levels were determined to be non-tolerated, with DLTs of febrile neutropenia (FN) (2 pts at 2.0 mg/m2/day and both pts at 2.25 mg/m2/day) and Grade 3 mucositis (both pts at 2.25 mg/m2/day). One out of 6 evaluable pts at 1.5 mg/m2/day also developed a DLT of FN. In an attempt to optimize the Phase 2 dose, an intermediate dose level of 1.75 mg/m2/day with G-CSF is currently being evaluated. The most commonly reported treatment-related adverse events (AEs) include those observed with other KSP inhibitors, such as hematological AEs (thrombocytopenia, neutropenia, anemia, leukopenia), fatigue, mucositis and other gastro-intestinal AEs. Pts displayed linear PK, a low clearance and a moderate volume of distribution, with moderate-to-high inter-individual variability in PK parameters. The median terminal elimination half life is 65 hours. The preliminary efficacy signal as a single agent is encouraging with 2 partial responses (PR) observed to date per IMWG and EBMT criteria in a heavily pretreated population (23 evaluable pts). A bortezomib-refractory pt with 8 prior lines of therapy, including a tandem transplant, treated at 1 mg/m2/day of ARRY-520 obtained a PR after Cycle 6, with urine protein and kappa light chain levels continuing to decline over time. He remains on-study after 15 months of ARRY-520 treatment. A pt with 2 prior lines of therapy, including prior carfilzomib, has obtained a PR after Cycle 8 at 2 mg/m2/day of ARRY-520, and she is currently ongoing after 4.5 months on therapy. Fifteen pts had a best response of stable disease (SD), including 1 pt with a thus far unconfirmed minimal response, and 6 had progressive disease. A total of 10 pts (43%) achieved a PR or SD lasting > 12 weeks. Several additional pts have shown other evidence of clinical activity, with decrease in paraproteins, increase in hemoglobin levels and regression of plasmacytomas. The median number of cycles is 4 (range 1–28+). Treatment activity has not correlated with any baseline characteristics or disease parameters to date. Conclusions: : The selective KSP inhibitor ARRY-520 has been well tolerated, and shows promising signs of single agent clinical activity in heavily pretreated pts with RR MM. Prophylactic G-CSF has enabled higher doses to be tolerated. No cardiovascular or liver enzyme toxicity has been reported. Enrollment is ongoing at 1.75 mg/m2/day with G-CSF support, and a planned Phase 2 part of the study will be initiated as soon as the MTD is determined. Complete Phase 1 data will be disclosed at the time of the meeting. Disclosures: Shah: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Research Funding. Off Label Use: Revlimid (lenalidomide) in combination with dexamethasone is indicated for the treatment of multiple myeloma patients who have received at least one prior therapy. Zonder:Millennium: Consultancy, Myeloma and Amyloidosis Patient Day Symposium – Corporate support from multiple sponsors for a one-day educational event, Research Funding; Celgene:; Novartis:; Proteolix: . Weber:novartis-unpaid consultant: Consultancy; Merck- unpaid consultant: Consultancy; celgene- none for at least 2 years: Honoraria; millenium-none for 2 years: Honoraria; celgene, Millenium, Merck: Research Funding. Wang:Celgene: Research Funding; Onyx: Research Funding; Millenium: Research Funding; Novartis: Research Funding. Kaufman:Celgene: Consultancy, Honoraria, Research Funding; Millenium: Consultancy, Honoraria; Merck: Research Funding; Genzyme: Consultancy. Walker:Array Biopharma: Employment, Equity Ownership. Freeman:Array Biopharma: Employment, Equity Ownership. Rush:Array Biopharma: Employment, Equity Ownership. Ptaszynski:Array Biopharma: Consultancy. Lonial:Millennium, Celgene, Bristol-Myers Squibb, Novartis, Onyx: Advisory Board, Consultancy; Millennium, Celgene, Novartis, Onyx, Bristol-Myers Squibb: Research Funding.

Phase 1 Study of CB-839, a First-in-Class, Glutaminase Inhibitor in Patients with Multiple Myeloma and Lymphoma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3059-3059 ◽  
Author(s):  
Dan T. Vogl ◽  
Anas Younes ◽  
Keith Stewart ◽  
Keith William Orford ◽  
Mark Bennett ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Research Funding ◽  
Blood Platelets ◽  
Safety Data ◽  
Employment Equity ◽  
Efficacy Data ◽  
Trough Concentrations ◽  
Equity Ownership

Abstract Background: Malignant cells alter metabolism in order to enable their highly anabolic state. In addition to a massive increase in glycolysis, malignant cells frequently become dependent on glutamine to feed the TCA cycle and provide key building blocks for cell growth and proliferation. CB-839 is a first-in-class potent and selective inhibitor of glutaminase (GLS), the first step in glutamine metabolism, that has broad in vitro and in vivo anti-tumor activity in solid and heme malignancies, including multiple myeloma. GLS inhibition with CB-839 induces apoptosis and/or growth arrest in multiple myeloma and lymphoma cell lines and is synergistic with pomalidomide and lenalidomide in vitro and as well as in multiple myeloma xenograft models in vivo. Methods: CX-839-002 is an ongoing Ph1 evaluation of escalating doses of CB-839 in patients with relapsed/refractory multiple myeloma (MM) or non-Hodgkins lymphoma (NHL) with the primary objective of assessing the safety profile and selecting a recommended Phase 2 dose (RP2D). Pharmacokinetics (PK) was monitored on Days 1 and 15. Initially, CB-839 was given three times daily (TID) without food, but based on PK and safety data generated across three Ph1 studies in patients with solid and heme malignancies, the drug is now being given twice daily (BID) with meals. Results: Safety data are available for a total of 14 patients (9 MM, 4 follicular lymphoma, 1 diffuse large B cell lymphoma) that have enrolled to date during the dose escalation (100-400 mg TID and 600 mg BID). The patients have received a median of 7 prior lines of systemic therapy. CB-839 has been well tolerated with only three subjects experiencing a Gr3/4 AEs considered possibly related to study drug and there have been no discontinuations due to AEs. A similar tolerability profile has been observed across three Ph1 studies for CB-839. With a total of 119 pts treated with CB-839 across the three studies, Gr3/4 drug-related AEs have occurred in 16 subjects (13%) and 4.3% of discontinuations were due to AEs. Reversible, asymptomatic elevations in transaminases have been the primary Gr3 AEs, occurring primarily on the TID schedule in 6/59 (10.2%) pts; only one occurred among 60 pts (1.7%) receiving the BID regimen. BID dosing with 600 mg was determined to be the RP2D and combination studies with pomalidomide and dexamethasone have been initiated. The half-life of CB-839 is ~4 hr, exposure increases with dose, and trough concentrations generally remain above the target threshold of 200 ng/mL for patients receiving the RP2D. Six of 8 MM pts that received ≥ 400 mg TID achieved steady state (D15) trough concentrations above the PK target threshold while 0 of 5 pts that received ≤ 250 mg TID achieved the PK threshold. Pharmacodynamic assessment of GLS activity in MM patients was consistent with a broader PK/PD assessment (across all 3 Ph1 studies), which established clear exposure-dependent inhibition of the target in peripheral blood platelets 4 hr after the first dose of CB-839, with >90% inhibition being maintained for most patients at the RP2D. Preliminary efficacy data include confirmed stable disease in 4 of 9 evaluable MM patients. Updated efficacy data and correlative studies on clinical samples will also be presented. The first pt treated with the combination of CB-839 and pomalidomide/dexamethasone (Pd) during dose escalation received 400 mg CB-839 BID, pomalidomide at 4 mg/day (D1-21) and dexamethasone at 40 mg on Days 1, 8, 15 and 22 of each 28-day cycle. This pt had a 71% decreased in urine M-protein and an 83% reduction in serum free light chain after the first 2 cycles of treatment. This pt had 11 prior lines of therapy but not pomalidomide and had two stem cell transplants and was progressing rapidly prior to study entry. The pt has tolerated the combination well and is continuing on study. Conclusions: CB-839 has been well tolerated at and above doses that produced robust inhibition of GLS in blood platelets and in tumors. Dosing BID with food has improved the PK profile and mitigated the frequency and severity of LFT elevations, which was the primary safety signal using TID dosing. Strong preclinical combination data, an excellent clinical safety profile, and initial data with CB-839 combined with Pd provide a strong rationale for continued development of CB-839 this combination in pts with relapsed/refractory multiple myeloma. Disclosures Vogl: Constellation Pharmaceuticals: Research Funding; Calithera Biosciences: Research Funding; Celgene Corporation: Consultancy; Acetylon Pharmaceuticals, Inc.: Research Funding; Millennium Pharmaceuticals: Research Funding; GSK: Research Funding. Younes:Celgene: Honoraria; Curis: Research Funding; Sanofi-Aventis: Honoraria; Seattle Genetics: Honoraria, Research Funding; Novartis: Research Funding; Janssen: Honoraria; Takeda Millenium: Honoraria; Bristol Meyer Squibb: Honoraria; Bayer: Honoraria; Incyte: Honoraria; Johnson and Johnson: Research Funding. Orford:Calithera Biosciences: Employment, Equity Ownership. Bennett:Calithera Biosciences: Employment, Equity Ownership. Siegel:Celgene Corporation: Consultancy, Speakers Bureau; Amgen: Speakers Bureau; Takeda: Speakers Bureau; Novartis: Speakers Bureau; Merck: Speakers Bureau. Berdeja:Curis: Research Funding; Acetylon: Research Funding; Novartis: Research Funding; Janssen: Research Funding; Takeda: Research Funding; BMS: Research Funding; Array: Research Funding; MEI: Research Funding; Abbvie: Research Funding; Celgene: Research Funding; Onyx: Research Funding.

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

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3145-3145 ◽  
Author(s):  
Paul G. Richardson ◽  
Myo Htut ◽  
Cristina Gasparetto ◽  
Jeffrey A. Zonder ◽  
Thomas G. Martin ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Peripheral Blood ◽  
Research Funding ◽  
Phase 1 ◽  
Single Agent ◽  
Advisory Board ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

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

QT Interval Effects and M-Protein Response in a Phase 1 Study of Siltuximab (Anti-IL-6 Monoclonal Antibody) in Patients with Monoclonal Gammopathy of Undetermined Significance, Smoldering Multiple Myeloma, or Indolent Multiple Myeloma.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2972-2972
Author(s):  
Sheeba K. Thomas ◽  
Alexander Suvorov ◽  
Lucien Noens ◽  
Oleg Rukavitsin ◽  
Joseph Fay ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Studies ◽  
Qt Interval ◽  
Research Funding ◽  
Phase 1 ◽  
Single Agent ◽  
M Protein ◽  
Qtc Interval ◽  
Employment Equity ◽  
Equity Ownership

Abstract Abstract 2972 Introduction Siltuximab is a chimeric monoclonal antibody that binds human interleukin (IL)-6 with high affinity. Formal assessments of siltuximab's effects on cardiac repolarization using triplicate electrocardiograms (ECGs) have not yet been performed in clinical studies. A phase 1 study was conducted to evaluate the effect of siltuximab, administered at the highest dose level used in clinical studies, on the QT interval in patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), or indolent multiple myeloma (IMM, i.e., asymptomatic MM with ≤3 lytic bone lesions but no other end organ damage). Methods Thirty patients with MGUS, SMM, or IMM who met the following criteria on ECG at screening: pulse 45−90 bpm, QTcF and QTcB ≤500 ms, QRS <100 ms, and PR <200 ms received siltuximab 15 mg/kg q3w as a 60 min IV infusion for 4 cycles. Patients were excluded for significant cardiac disease. ECGs and pharmacokinetics assessment were performed at Cycle 1 (pre-infusion [baseline]; end of infusion; and 1, 3, and 24 hrs post-infusion) and at Cycle 4 (pre-infusion, end of infusion, and 1 hr post-infusion). At all timepoints, triplicate 12-lead ECGs were conducted and evaluated by a central cardiology laboratory. No effect on QTc interval was concluded if the upper limit of the least square (LS) mean 90% confidence interval (CI) for the change from baseline QTc at each time point was <20 ms. Safety data were also collected. Preliminary assessment of clinical activity was performed using M-protein measurements from local laboratories. Patients achieving a 50% reduction from baseline in M-protein after 4 cycles were eligible for extended siltuximab therapy (15 mg/kg q4w). Results Thirty patients (14 MGUS, 15 SMM, 1 IMM) with median age 59.5 (range 24, 79) yrs were enrolled. Median serum protein electrophoresis was 1.21 (range 0, 5.4) g/dL, and median urine protein electrophoresis was 0 (range 0, 267) mg/24 hrs. Twenty-eight patients completed all 4 treatment cycles, among whom 27 were evaluable for the primary endpoint of QT interval assessment. The maximum mean increase in QTc from baseline occurred 3 hrs after the Cycle 1 infusion (QTcF = 3.2 ms [LS mean 90% CI −0.01, 6.45]; QTcB = 2.7 ms [LS mean 90% CI −0.69, 6.14]). At all other time points for both QTcF and QTcB, the mean increase from baseline was ≤1.5 ms and the upper limit of LS mean 90% CI was ≤5.07 ms. An effect of siltuximab on QTc interval was therefore ruled out. Furthermore, no patient had a QTcF or QTcB increase from baseline >30 ms, and no correlation was observed between siltuximab serum concentrations and change from baseline in QTcB or QTcF. Twenty (67%) of 30 treated patients had ≥1 adverse events (AEs). AEs reported by ≥10% of patients were nausea, fatigue (20% each); thrombocytopenia, headache (each 13%); dyspnea, leukopenia, neutropenia, paraesthesia, and upper respiratory tract infection (each 10%). The majority of AEs were grade ≤2. However, 8 (27%) patients had ≥1 AE grade ≥3: neutropenia (n=3); hypertriglyceridemia, hypertension, hypotension, leukopenia, and myalgia (each n=1); and 1 patient had grade 3 ascites, cellulitis, peripheral edema, portal hypertension, and hepatic cirrhosis (diagnosis made during hospitalization). This patient discontinued treatment due to cellulitis (possibly related to siltuximab) with peripheral edema and ascites (not related to siltuximab). A second patient discontinued treatment due to grade 2 atrial fibrillation that was not related to siltuximab. No severe infusion reactions or deaths were reported. After the first 4 cycles (3 mos), 3 MGUS patients achieved an M-protein response (≥50% reduction from baseline), and 9 patients (3 MGUS, 5 SMM, 1 IMM) had minor responses (≥25% and <50% reduction from baseline). Two patients who qualified for extended treatment with siltuximab continued to receive therapy (17 and 6 cycles, respectively) at the time of database lock. Conclusion Siltuximab, given at the highest dose level used in clinical studies, did not affect the QTc interval. Overall safety was similar to what has been previously reported for other single-agent siltuximab studies. M-protein responses were seen by local laboratory assessment within the first 4 cycles. A randomized phase 2 study is ongoing to further evaluate the efficacy and safety of single-agent siltuximab in high-risk SMM. Disclosures: Thomas: Millenium: Research Funding; Novartis: Research Funding; Immunomedics: Research Funding; Johnson & Johnson: Research Funding; Celgene: Research Funding; Onyx: Membership on an entity's Board of Directors or advisory committees. van de Velde:Johnson & Johnson: Employment, Equity Ownership. Bandekar:Johnson & Johnson: Employment, Equity Ownership. Puchalski:Johnson & Johnson: Employment, Equity Ownership. Qi:Johnson & Johnson: Employment, Equity Ownership. Uhlar:Johnson & Johnson: Employment, Equity Ownership.

scholarly journals Dreamm-3: A Phase 3, Open-Label, Randomized Study to Evaluate the Efficacy and Safety of Belantamab Mafodotin (GSK2857916) Monotherapy Compared with Pomalidomide Plus Low-Dose Dexamethasone (Pom/Dex) in Participants with Relapsed/Refractory Multiple Myeloma (RRMM)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1900-1900 ◽  
Author(s):  
Katja Weisel ◽  
Thomas G Hopkins ◽  
Doug Fecteau ◽  
Weichao Bao ◽  
Corinne Quigley ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Antibody ◽  
Research Funding ◽  
Standard Of Care ◽  
Efficacy And Safety ◽  
Open Label ◽  
Employment Equity ◽  
Phase 3 ◽  
Refractory Multiple Myeloma ◽  
Equity Ownership

Background: Belantamab mafodotin is a humanized, afucosylated, anti-B-cell maturation antigen (BCMA) monoclonal antibody conjugated to monomethyl auristatin F via a maleimidocaproyl linker (mcMMAF). Upon binding to BCMA on the surface of plasma cells, it is rapidly internalized and the cytotoxic moiety (cys-mcMMAF) is released, antibody-dependent cellular cytotoxicity is enhanced, and immunogenic cell death occurs. In vitro and in vivo cytotoxic activity against both myeloma cell lines and primary patient cells has been demonstrated in preclinical studies. In the first-in-human phase 1 study (DREAMM-1/BMA117159, NCT02064387), belantamab mafodotin had a manageable safety profile and demonstrated a rapid, deep, and durable clinical response as a monotherapy in patients with relapsed/refractory multiple myeloma (RRMM). In a cohort of 35 heavily pretreated patients with RRMM (57% with ≥5 lines of prior therapy) who received belantamab mafodotin 3.4 mg/kg by intravenous (IV) infusion every 3 weeks (Q3W) overall response rate (ORR) of 60% (95% confidence interval [CI]: 42.1, 76.1) was demonstrated. The median progression-free survival (PFS) was 12.0 months (95% CI: 3.1, not estimable [NE]) and the median duration of response (DoR) was 14.3 months (95% CI: 10.6, NE). Belantamab mafodotin monotherapy in patients with RRMM is being further evaluated against the standard-of-care pomalidomide/dexamethasone (Pom/Dex) regimen in the DREAMM-3 study. Methods: The phase 3, multicenter, randomized, open-label DREAMM-3 study will evaluate the efficacy and safety of belantamab mafodotin monotherapy compared with Pom/Dex, an established standard-of-care regimen in RRMM. In this global study, patients treated with ≥2 prior lines of therapy, including ≥2 consecutive cycles of both lenalidomide and a proteasome inhibitor, and refractory to the last line of treatment, will be eligible for inclusion. Participants with prior allogeneic transplant will be excluded, as will those with prior exposure to BCMA-targeted therapies and Pom. Approximately 320 participants will be randomized (2:1) to receive either belantamab mafodotin or Pom/Dex and will be stratified by age, exposure to anti-CD38 therapy, and number of prior lines of treatment. Belantamab mafodotin will be administered IV Q3W, at the dose confirmed in the ongoing DREAMM-2 study (NCT03525678). Pom will be administered orally at 4 mg on Days 1-21 of each 28-day cycle, with Dex 40 or 20 mg (depending on age) on Days 1, 8, 15, and 22. Treatment in both arms will continue until progressive disease, unacceptable toxicity, or death. The primary endpoint is PFS, and overall survival is a key secondary endpoint. Additional secondary endpoints include ORR, time to response, minimal residual disease negativity rate (10-5 threshold assessed by next-generation sequencing), DoR, safety, and health-related quality of life. Bone marrow and blood samples will be collected for biomarker research. The study is planned to start in late 2019. Acknowledgments: Editorial assistance was provided by Sarah Hauze, PhD, at Fishawack Indicia Ltd, UK, and funded by GlaxoSmithKline. Study is funded by GlaxoSmithKline (ID: 207495); drug linker technology is licensed from Seattle Genetics; monoclonal antibody is produced using POTELLIGENT Technology licensed from BioWa. Disclosures Weisel: Sanofi: Consultancy, Honoraria, Research Funding; Adaptive Biotech: Consultancy, Honoraria; GSK: Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Juno: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Hopkins:GSK: Employment, Equity Ownership. Fecteau:GSK: Employment, Equity Ownership. Bao:GSK: Employment, Equity Ownership. Quigley:GSK: Employment, Equity Ownership. Jewell:GSK: Employment, Equity Ownership. Nichols:GSK: Employment, Equity Ownership. Opalinska:GSK: Employment, Equity Ownership.

FcRL5 as a Target of Antibody-Drug Conjugates for the Treatment of Multiple Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3836-3836 ◽  
Author(s):  
Andrew G. Polson ◽  
Bing Zheng ◽  
Kristi Elkins ◽  
Jeffery Lau ◽  
Mary Ann T. Go ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
B Cells ◽  
Cell Line ◽  
Research Funding ◽  
Employment Equity ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Equity Ownership ◽  
Antibody Drug

Abstract Abstract 3836 Poster Board III-772 Antibody-drug conjugates (ADCs), potent cytotoxic drugs linked to antibodies via specialized chemical linkers, provide a means to increase the effectiveness of chemotherapy by targeting the drug to neoplastic cells while reducing side effects. Target selection is a key component to the success of an ADC. In addition to expression on the tumor, the target should have limited expression on normal tissues. The most prevalent and best-studied surface antigens on multiple myeloma (MM) cells, CD138, CD38, CD72, and CD56, all have relatively broad expression patterns that may lead to target-dependent toxicities with ADCs. We have previously shown that FcRL5/FcRH5/IRTA2 is expressed only on B-cells and plasma cells. Here we show that FcRL5 is expressed on the surface of MM cells from 85% of patients and thus could be a target for antibody and ADC treatments of MM. As experience in humans with anti-CD20 antibodies suggests that depletion of B-cells does not present a major safety issue, FcRL5 appears to have an excellent expression pattern as an ADC target for MM. Internalization of target antigens is known to increase the efficacy of ADCs and we found that FcRL5 is internalized upon antibody binding, an ideal trait. We made two different ADCs consisting of anti-FcRL5 antibodies 1) conjugated through cysteines to monomethylauristatin E (MMAE) by a maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl (MC-vcPAB) linker that is designed to be cleaved by cathepsins (Anti-FcRL5-MC-vcPAB-MMAE); and 2) conjugated via lysines to the maytansinoid DM4 through a disulified linker designed to be cleaved by reducing conditions (anti-FcRL5-SPDB-DM4). These ADCs were tested for cell killing in vitro and in xenograft studies using OPM2 cells stably expressing FcRL5. While unconjugated anti-FcRH5 and control ADCs were not effective, anti-FcRL5-MC-vcPAB-MMAE and anti-FcRL5-SPDB-DM4 were effective at killing this MM cell line both in vitro and in vivo. Furthermore, the anti-FcRL5-SPDB-DM4 conjugate was effective in a SCID-rabbit bone model of MM using the LD cell line. These data suggest that FcRL5 ADCs could be an effective treatment for MM. Disclosures: Polson: Genentech, Inc.: Employment, Equity Ownership. Zheng:Genentech, Inc.: Employment, Equity Ownership. Elkins:Genentech, Inc.: Employment, Equity Ownership. Lau:Genentech, Inc.: Employment, Equity Ownership. Go:Genentech, Inc.: Employment, Equity Ownership. Scales:Genentech, Inc.: Employment, Equity Ownership. Yu:Genentech, Inc.: Employment, Equity Ownership. Chesi:Genentech, Inc.: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Merck: Research Funding. Bergsagel:Genentech, Inc.: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Merck: Research Funding. Ebens:Genentech, Inc.: Employment, Equity Ownership, Patents & Royalties.

scholarly journals Concomitant Suppression of IKZF1, IRF4 and MYC Contribute to the Anti-Tumor Activity of the BET Inhibitor, Cpi-0610, in Disease Models of Multiple Myeloma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3320-3320 ◽  
Author(s):  
Ka Tat Siu ◽  
Janani Ramachandran ◽  
Andrew J. Yee ◽  
Homare Eda ◽  
Loredana Santo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Research Funding ◽  
Employment Equity ◽  
Advisory Committees ◽  
Bet Inhibitor ◽  
Bet Inhibitors ◽  
Equity Ownership ◽  
Anti Tumor Activity

Abstract Inhibition of the bromodomain and extra-terminal (BET) proteins is a promising therapeutic strategy for various hematologic malignancies. Previous studies suggest that BET inhibitors constrain tumor cell proliferation and survival mainly through suppression of MYC transcription and activity. However, suppression of the transcription of additional genes also contributes to the anti-tumor activity of BET inhibitors but is less well understood. Here we investigated the therapeutic potential of CPI-0610, a novel BET inhibitor that is currently in a phase I clinical trial in relapsed multiple myeloma (MM) (ClinicalTrials.gov Identifier: NCT02157636). CPI-0610 displays potent in vitro cytotoxicity against MM cell lines and patient-derived MM cells by inducing G1 cell cycle arrest and caspase-dependent apoptosis. Furthermore, CPI-0610-mediated BET inhibition overcomes the protective effects conferred by cytokines and bone marrow stromal cells. We also confirmed the in vivo efficacy of CPI-0610 in a MM xenograft mouse model. CPI-0610 significantly delayed tumor growth and increased the survival of MM-bearing SCID mice. Our study found IKZF1 and IRF4 to be among the primary targets of CPI-0610, along with MYC. These findings indicate that BET inhibition not only results in a robust reduction of MYC transcription and activity but also suppresses the expression of IKZF1 and IRF4 in MM. Given that immunomodulatory drugs stabilize cereblon and facilitate Ikaros degradation in MM cells, we combined it with CPI-0610. Combination studies of CPI-0610 with lenalidomide or pomalidomide show in vitro synergism, in part due to concomitant suppression of IKZF1, IRF4, and MYC, providing a rationale for clinical testing of this drug combination in MM patients. Disclosures Mertz: Constellation Pharmaceuticals, Inc.: Employment, Equity Ownership. Sims:Constellation Pharmaceuticals, Inc.: Employment, Equity Ownership. Cooper:Constellation Pharmaceuticals, Inc.: Employment, Equity Ownership. Raje:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Eli Lilly: Research Funding.

scholarly journals A Favorable BCL-2 Family Expression Profile May Explain the Increased Susceptibility of the t(11;14) Multiple Myeloma Subgroup to Single Agent Venetoclax

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5613-5613 ◽  
Author(s):  
Jenny Wu ◽  
Jeremy Ross ◽  
Franklin V. Peale ◽  
John D Shaughnessy ◽  
Ryan K Van Laar ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Research Funding ◽  
Expression Profiles ◽  
Single Agent ◽  
Objective Response ◽  
Hematologic Malignancies ◽  
Lymphocytic Leukemia ◽  
Employment Equity ◽  
Equity Ownership ◽  
Increased Susceptibility

Abstract Background: In preclinical studies, multiple myeloma (MM) cells are sensitive to selective inhibition of the pro-survival protein BCL-2 by venetoclax (VEN). Resistance to VEN in these models was mediated through BCL-XL and MCL-1, and MCL-1 mediated resistance was neutralized by co-treatment with the proteasome inhibitor bortezomib (BTZ). MM cells harboring the t(11;14) translocation have a higher ratio of BCL-2 relative to MCL-1 mRNA and increased sensitivity to VEN alone, compared to cells with other cytogenetic abnormalities, suggesting that MM subgroups with a favorable BCL-2 family profile might be particularly sensitive to VEN. Clinically, VEN has shown activity in CLL, a disease typically expressing high BCL-2 and low BCL-XL and MCL-1 expression. In MM, VEN is being evaluated as a single agent (NCT01794520) and in combination with BTZ and dexamethasone (Dex) (NCT01794507, NCT02755597) in relapsed/refractory (R/R) patients. As a single agent, improved objective response rates were observed in patients with R/R t(11;14) MM (40% in t(11;14) vs 6% in non-t(11;14)-). In the BTZ/Dex combination study, patients with high BCL-2 expression had an increased objective response rate. Thus, BCL-2 family profiling may explain increased susceptibility of certain MM subgroups to antitumor activity of VEN both as a single agent and in combination. We analyzed MM subgroups for expression of BCL-2 family members to better understand and identify the patient population that can benefit with VEN. Methods: We used publically available data (GSE4581; GSE9782) to analyze BCL-2 family mRNA expression within molecular/cytogenetic defined subgroups among newly diagnosed (NDMM n=414), and R/R (n=264) MM patients, and in comparison to other hematological malignancies (genealogic database). Results: BCL-2, BCL-XL and MCL-1 expression was assessed in MM and compared with 12 major hematologic malignancies. Based on median expression, BCL-2 in MM ranked 6th of 12 tested, with highest BCL-2 expression observed in small lymphocytic leukemia and mantle cell lymphoma. In MM, BCL-2 expression varied significantly across molecular and cytogenetic subgroups. Highest expression was among patients with t(11;14) molecular subtypes (CD1, CD2), in addition to subtypes that are not enriched with t(11;14) like the hyperdiploid and low bone disease subtypes, and lowest in the high-risk subtypes (proliferation, MMSET, MAF/MAFB) (p=0.0001), both in NDMM and R/R MM. BCL-XL and MCL-1 were highly expressed in MM relative to other hematologic malignancies. Expression of BCL-XL and MCL-1 were lowest in the t(11;14) MM population (both p<0.001). Correspondingly, t(11;14) MM was enriched for the highest ratios of BCL-2/MCL-1 (p<0.0001) and BCL-2/BCL-XL (p<0.0001), further supporting the strong single agent VEN activity observed in these patients in clinical study. The t(11;14) positive CD2 subtype can be further characterized by high expression of CD20, (p<0.0001, CD2 vs other), and by other B-cell phenotypic markers (high for PAX5, CD79A and VPREB, and low for CD56). Thus, the CD2 molecular subtype may identify a CLL-like subset of t(11;14) MM that is uniquely susceptible to VEN single agent activity. Finally, when we assessed BCL-2 family expression in R/R MM across lines of treatment, we found patients with 1-3 prior lines of therapy had a higher BCL-2/MCL-1 ratio (p<0.001) compared to patients with greater lines of therapy, due primarily to lower MCL-1 expression (p<0.001), but similar BCL-2 expression. Conclusions: Our analysis suggests that MM subgroups are associated with distinct BCL-2 family expression profiles, and the t(11;14) subgroup amongst MM subgroups may be particularly suited for single agent VEN activity due to a high BCL-2/MCL-1 and BCL-2/BCL-XL ratio. In the non-t(11;14) MM subgroups, VEN treatment in earlier lines of therapy, as well as combination strategies with agents that will down-modulate BCL-XL and/or MCL-1, such as BTZ, may enable maximum VEN activity, and will be further assessed in clinical studies. Disclosures Wu: Genentech: Employment. Ross:AbbVie: Employment, Equity Ownership. Peale:Genentech: Employment, Equity Ownership. Shaughnessy:Signal Genetics: Consultancy, Equity Ownership. Van Laar:Signal Genetics, Inc.: Employment. Morgan:Takeda: Consultancy, Honoraria; Janssen: Research Funding; Bristol Meyers: Consultancy, Honoraria; Univ of AR for Medical Sciences: Employment; Celgene: Consultancy, Honoraria, Research Funding. Venstrom:Genentech: Employment. Punnoose:Genetech, Inc.: Employment.

scholarly journals Evaluation of Combination Tagraxofusp (SL-401) and Hypomethylating Agent (HMA) Therapy for the Treatment of Chronic Myelomonocytic Leukemia (CMML)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1809-1809
Author(s):  
Aishwarya Krishnan ◽  
Bing Li ◽  
Maria Pagane ◽  
Erin McGovern ◽  
Zoe Stone-Molloy ◽  
...  
Keyword(s):  
Stem Cell ◽  
Research Funding ◽  
Mononuclear Cells ◽  
Plasmacytoid Dendritic Cell ◽  
Single Agent ◽  
Cell Transplant ◽  
Employment Equity ◽  
Equity Ownership ◽  
Myelomonocytic Leukemia

Abstract Background: Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder that is characterized by cytopenias, organomegaly, constitutional symptoms, autoimmune phenomena, and ultimately progression to acute myeloid leukemia (AML). The only known cure for CMML remains allogeneic stem cell transplant. Aside from stem cell transplant, currently utilized therapeutic modalities include hydroxyurea, erythropoietin stimulating agents (ESAs) and hypomethylating agents (HMAs). Azacitidine (AZA) and Decitabine (DAC) have been utilized to treat CMML patients, particularly those with cytopenias, with variable efficacy such that complete response only occurs in a minority of patients. Recent work has identified CD123 (interleukin-3 receptor-α; IL-3R-α) as a potential therapeutic target in myeloid malignancies. CD123 is expressed in a variety of myeloid malignancies, including AML, myelodysplastic syndrome (MDS) and CMML. Further, plasmacytoid dendritic cell infiltrates (pDC) which are known to infiltrate the bone marrow in CMML, express CD123. Tagraxofusp (Elzonris™, SL-401) is a targeted therapy directed to CD123, comprised of recombinant IL-3 fused to a truncated diphtheria toxin payload. Clinical studies of tagraxofusp are being carried out in a variety of hematologic malignancies, including blastic plasmacytoid dendritic cell neoplasm (BPDCN), myelofibrosis (MF), and CMML. Data from an ongoing Phase I/II trial of tagraxofusp in relapsed/refractory CMML (n=16 patients) demonstrated spleen size reductions in 100% (8/8) patients with baseline splenomegaly and 2 bone marrow complete responses (BMCRs). Thus, tagraxofusp appears to have single agent clinical activity in CMML. Given this activity, and the known activity of HMAs in CMML, we sought to determine if combination HMA and tagraxofusp may provide added therapeutic utility over HMA therapy alone. Methods: To address this question, we performed preclinical studies using human leukemia cell lines as well as mononuclear cells from primary patient CMML samples. In order to determine active concentrations of both AZA and tagraxofusp in vitro, cell viability assays were performed. K562 cells, which have been previously demonstrated to express CD123, were first studied for sensitivity to AZA and tagraxofusp. The IC50 of AZA was 772uM and 4.8nM for tagraxofusp (Figure 1A). We next performed viability assays using fresh mononuclear cells from CMML patients. The IC50 of single agent AZA was 1442uM, whereas the IC50 of combination AZA and tagraxofusp (at a concentration of 4.8nM) was 725uM. As well, adding tagraxofusp at a concentration of 4.8nM to 1uM AZA in this assay induced a significant reduction in cell viability (Figure 1B; p<0.05). In colony assays, combination AZA and tagraxofusp significantly reduced colony formation when compared to single agent AZA alone (Figure 1 C-E, p<0.05). This effect was observed in samples with a relatively high sensitivity to AZA (Figure 1D) as well as in less sensitive samples (Figure 1E). Addition of AZA to increasing concentrations of tagraxofusp demonstrated a similar significant reduction in colony formation (Figure 1 F, p<0.05). Importantly, a combination effect was observed across samples of different genotypes including patient samples with high risk genotypes, including NRAS/ASXL1/TET2 (Figure 1E) and mutations in SRSF2/TET2/STAG2 (Figure 1C). Conclusions: Current therapeutic options for CMML are limited and CMML remains a significant unmet medical need. Although HMA therapy has demonstrated efficacy in CMML, the effects are often limited in extent and duration. Our preclinical data, including in primary CMML samples, demonstrates a potential therapeutic role for the combination of an HMA and tagraxofusp in CMML. Further in vitro data from primary patient samples, including impact of single and dual agent therapy on immunophenoytpe and clonal architecture, as well as in vivo efficacy data, will be presented. Disclosures Chen: Stemline Therapeutics: Employment, Equity Ownership. Brooks:Stemline Therapeutics: Employment, Equity Ownership. Rampal:Constellation: Research Funding; Celgene: Honoraria; Jazz: Consultancy, Honoraria; Incyte: Honoraria, Research Funding; Stemline: Research Funding.

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