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Arthur E Frankel - One of the best experts on this subject based on the ideXlab platform.

  • in vivo and in vitro sensitivity of blastic plasmacytoid dendritic cell neoplasm to sl 401 an interleukin 3 Receptor targeted biologic agent
    Haematologica, 2015
    Co-Authors: Fanny Angelotdelettre, Arthur E Frankel, Eric K Rowinsky, Anne Roggy, Baptiste Lamarthee, Estelle Seilles, Sabeha Biichle, Bernard Royer, Eric Deconinck, Christopher L Brooks
    Abstract:

    Blastic plasmacytoid dendritic cell neoplasm is an aggressive malignancy derived from plasmacytoid dendritic cells. There is currently no accepted standard of care for treating this neoplasm, and therapeutic strategies have never been prospectively evaluated. Since blastic plasmacytoid dendritic cell neoplasm cells express high levels of Interleukin-3 Receptor α chain (IL3-Rα or CD123), antitumor effects of the Interleukin-3 Receptor-targeted drug SL-401 against blastic plasmacytoid dendritic cell neoplasm were evaluated in vitro and in vivo. The cytotoxicity of SL-401 was assessed in patient-derived blastic plasmacytoid dendritic cell neoplasm cell lines (CAL-1 and GEN2.2) and in primary blastic plasmacytoid dendritic cell neoplasm cells isolated from 12 patients using flow cytometry and an in vitro cytotoxicity assay. The cytotoxic effects of SL-401 were compared to those of several relevant cytotoxic agents. SL-401 exhibited a robust cytotoxicity against blastic plasmacytoid dendritic cell neoplasm cells in a dose-dependent manner. Additionally, the cytotoxic effects of SL-401 were observed at substantially lower concentrations than those achieved in clinical trials to date. Survival of mice inoculated with a blastic plasmacytoid dendritic cell neoplasm cell line and treated with a single cycle of SL-401 was significantly longer than that of untreated controls (median survival, 58 versus 17 days, P<0.001). These findings indicate that blastic plasmacytoid dendritic cell neoplasm cells are highly sensitive to SL-401, and support further evaluation of SL-401 in patients suffering from blastic plasmacytoid dendritic cell neoplasm.

  • sl 401 and sl 501 targeted therapeutics directed at the interleukin 3 Receptor inhibit the growth of leukaemic cells and stem cells in advanced phase chronic myeloid leukaemia
    British Journal of Haematology, 2014
    Co-Authors: Olga Frolova, Christopher L Brooks, Eric K Rowinsky, Juliana Benito, Rui Yu Wang, Borys Korchin, Jorge E Cortes, Hagop M Kantarjian, Michael Andreeff, Arthur E Frankel
    Abstract:

    While imatinib and other tyrosine kinase inhibitors (TKIs) are highly efficacious in the treatment of chronic myeloid leukaemia (CML), some patients become refractory to these therapies. After confirming that Interleukin-3 Receptor (IL3R, CD123) is highly expressed on CD34(+) /CD38(-) BCR-ABL1(+) CML stem cells, we investigated whether targeting IL3R with diphtheria toxin (DT)-IL3 fusion proteins SL-401 (DT388 -IL3) and SL-501 (DT388 -IL3[K116W]) could eradicate these stem cells. SL-401 and SL-501 inhibited cell growth and induced apoptosis in the KBM5 cell line and its TKI-resistant KBM5-STI subline. Combinations of imatinib with these agents increased apoptosis in KBM5 and in primary CML cells. In six primary CML samples, including CML cells harbouring the ABL1 T315I mutation, SL-401 and SL-501 decreased the absolute numbers of viable CD34(+) /CD38(-) /CD123(+) CML progenitor cells by inducing apoptosis. IL3-targeting agents reduced clonogenic growth and diminished the fraction of primitive long-term culture-initiating cells in samples from patients with advanced phase CML that were resistant to TKIs or harboured an ABL1 mutation. Survival was also extended in a mouse model of primary TKI-resistant CML blast crisis. These data suggest that the DT-IL3 fusion proteins, SL-401 and SL-501, deplete CML stem cells and may increase the effectiveness of current CML treatment, which principally targets tumour bulk.

  • activity of sl 401 a targeted therapy directed to interleukin 3 Receptor in blastic plasmacytoid dendritic cell neoplasm patients
    Blood, 2014
    Co-Authors: Arthur E Frankel, Bruno C Medeiros, Naveen Pemmaraju, Francine Garnacheottou, Stephen J Forman, Hetty E Carraway, Olga Frankfurt, Xuezhong A Yang, Marina Konopleva, Fanny Angelotdelettre
    Abstract:

    This is the first prospective study of treatment of patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN), an aggressive hematologic malignancy derived from plasmacytoid dendritic cells that typically involves the skin and rapidly progresses to a leukemia phase. Despite being initially responsive to intensive combination chemotherapy, most patients relapse and succumb to their disease. Because BPDCN blasts overexpress the Interleukin-3 Receptor (IL3R), the activity of SL-401, diptheria toxin (DT)388IL3 composed of the catalytic and translocation domains of DT fused to IL3, was evaluated in BPDCN patients in a phase 1-2 study. Eleven patients were treated with a single course of SL-401 at 12.5 μg/kg intravenously over 15 minutes daily for up to 5 doses; 3 patients who had initial responses to SL-401 received a second course in relapse. The most common adverse events including fever, chills, hypotension, edema, hypoalbuminemia, thrombocytopenia, and transaminasemia were transient. Seven of 9 evaluable (78%) BPDCN patients had major responses including 5 complete responses and 2 partial responses after a single course of SL-401. The median duration of responses was 5 months (range, 1-20+ months). Further studies of SL-401 in BPDCN including those involving multiple sequential courses, alternate schedules, and combinations with other therapeutics are warranted. This trial is registered at clinicaltrials.gov as #NCT00397579.

  • activity and tolerability of sl 401 a targeted therapy directed to the interleukin 3 Receptor on cancer stem cells and tumor bulk as a single agent in patients with advanced hematologic malignancies
    Journal of Clinical Oncology, 2013
    Co-Authors: Arthur E Frankel, Christopher Brooks, David A Rizzieri, Marina Konopleva, Donna E Hogge, Thomas P Cirrito, Steven M Kornblau, Gautam Borthakur, Carol Bivins, Guillermo Garciamanero
    Abstract:

    7029^ Background: SL-401 is a novel biologic targeted therapy directed to the Interleukin-3 Receptor (IL-3R). IL-3R is overexpressed on cancer stem cells (CSCs) and tumor bulk relative to normal he...

  • a diphtheria toxin interleukin 3 fusion protein synergizes with tyrosine kinase inhibitors in killing leukemic progenitors from bcr abl positive acute leukemia
    Leukemia Research, 2010
    Co-Authors: Hyun Pyo Kim, Arthur E Frankel, Donna E Hogge
    Abstract:

    Abstract Despite initial remissions, most patients with Ph chromosome positive (Ph + ) acute leukemia (AL) become refractory to tyrosine kinase inhibitors (TKIs) such as imatinib and dasatinib. This study was designed to determine if targeting the Interleukin-3 Receptor (IL-3R) with a diphtheria toxin fusion protein (DT 388 IL3) would improve the effectiveness of TKIs against Ph + AL cells. IL-3R subunits were detected on most Ph + cells and the IC50 for killing of colony forming cell (CFC) with DT 388 IL3 correlated with the level of IL-3Rα subunit by FACS. DT 388 IL3 synergized with both imatinib and dasatinib for killing of malignant CFCs. Long-term suspension culture-initiating cells (SC-ICs) and quiescent leukemic cells (G 0 in cell cycle) also were studied and synergistic interactions were again demonstrated. Thus, cotreatment with TKIs and DT 388 IL3 is much more effective in eliminating Ph + leukemic progenitors that express IL-3R than either agent alone.

Eric K Rowinsky - One of the best experts on this subject based on the ideXlab platform.

  • lead in stage results of a pivotal trial of sl 401 an interleukin 3 Receptor il 3r targeting biologic in patients with blastic plasmacytoid dendritic cell neoplasm bpdcn or acute myeloid leukemia aml
    Blood, 2015
    Co-Authors: Kendra L Sweet, Eric K Rowinsky, Naveen Pemmaraju, Andrew A Lane, Anthony S Stein, Sumithira Vasu, William Blum, David A Rizzieri, Eunice S Wang, Michael Szarek
    Abstract:

    Background: SL-401 is a novel biologic delivering a truncated diphtheria toxin, a highly potent protein synthesis inhibitor, to the IL-3R that is overexpressed on cancer stem cells and tumor bulk in BPDCN, AML and other hematologic malignancies. The agent is being further evaluated in relapsed/refractory (r/r) BPDCN based on robust activity in BPDCN pts treated with a single cycle at 12 µg/kg/day x 5 (78% ORR, 55% CR; Frankel, Blood 2014). The objectives of the lead-in stage of this trial, which includes a pivotal evaluation in r/r BPDCN, were to evaluate the safety, pharmacokinetics (PK), and preliminary activity of multiple cycles, and confirm the dose for the BPDCN study and further AML studies. Methods & Results: To date, 17 adults (9 BPDCN; 8 AML; median ages: All 63; BPDCN 69; AML 53), 15 of whom are evaluable for dose-limiting toxicity (DLT), have received 57+ cycles (range, 1-12+) of SL-401 as a 15 min infusion daily for up to 5 days every 3 weeks at 7 (6 pts/29+ cycles), 9 (3 pts/9 cycles) & 12 µg/kg/day (8 pts/19+ cycles). Two BPDCN pts had DLTs of capillary leak syndrome (CLS; Gr 5 [7 µg/kg/d]; Gr 4 [12 µg/kg/d]) in cycle 1 as manifested by decreased serum albumin during treatment followed by symptomatic CLS; both had rapid improvement of skin only disease but did not complete formal end-of-cycle assessments and are not evaluable for response. No other DLTs have occurred and the maximum tolerated dose (MTD) has not been identified. Measures, successful to date in preventing CLS, have been implemented to suspend dosing within a cycle for early CLS (manifested by weight gain and/or decreased albumin) and have allowed those pts to proceed to full 5-day dosing in subsequent cycles. Transient Gr 3 transaminase elevations, largely limited to cycle 1, have also occurred. Cumulative side effects have not been observed over multiple cycles. Five (71%) of 7 evaluable BPDCN pts had major objective responses, including complete responses. Four of 5 BPDCN pts with bone marrow involvement (range 15-80% blast count) had normalization to ≤ 5% blasts, and robust resolution of extensive, symptomatic skin lesions, lymphadenopathy, and soft tissue disease have also been noted, often within days of starting treatment. Several BPDCN pts with objective responses are receiving continued therapeutic benefit with successive cycles. Three r/r AML pts had stable disease for 6-12+ cycles, one of whom resolved transfusion dependence. Preliminary PK studies indicate inter-subject variability, increasing exposure from day 1 to 5 of cycle 1, and generally increased exposure in BPDCN relative to AML pts. Conclusions: Multiple cycles of SL-401 are feasible and confer an acceptable safety profile at doses up to 12 µg/kg/day, which, along with safety measures to prevent CLS, will be used in a pivotal stage of this study in r/r BPDCN. Because of limited toxicity and evidence of protracted disease stabilization (up to 9+ mo) in several AML pts, further SL-401 dose escalation in AML is ongoing. Major responses in BPDCN and stabilization in AML indicate that targeting of IL-3R expressing cells via SL-401 has potential for sustained anticancer activity in aggressive myeloid malignancies. Disclosures Pemmaraju:Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. Lane:Stemline Therapeutics, Inc.: Research Funding. Stein:Amgen: Speakers Bureau. Blum:Celator: Consultancy; Celgene: Consultancy; Boerhinger Ingelheim: Consultancy. Rizzieri:Teva: Other: ad board, Speakers Bureau; Celgene: Other: ad board, Speakers Bureau. Wang:Immunogen: Research Funding. Rowinsky:Stemline Therapeutics: Employment, Equity Ownership. Szarek:Stemline Therapeutics: Employment. Brooks:Stemline Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties. Disalvatore:Stemline Therapeutics: Employment. Liu:Stemline Therapeutics: Employment. Duvic:Cell Medica Ltd: Consultancy; Array Biopharma: Consultancy; Oncoceutics: Research Funding; Spatz Foundation: Research Funding; Rhizen Pharma: Research Funding; Allos (spectrum): Research Funding; Soligenics: Research Funding; Eisai: Research Funding; MiRagen Therapeutics: Consultancy; Huya Bioscience Int9l: Consultancy; Therakos: Research Funding, Speakers Bureau; Celgene: Membership on an entity9s Board of Directors or advisory committees; Seattle Genetics: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Millennium Pharmaceuticals: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Kyowa Hakko Kirin, Co: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Innate Pharma: Research Funding; Tetralogics SHAPE: Research Funding. Schwartz:Stemline Therapeutics, Inc.: Employment, Equity Ownership. Konopleva:Novartis: Research Funding; AbbVie: Research Funding; Stemline: Research Funding; Calithera: Research Funding; Threshold: Research Funding.

  • in vivo and in vitro sensitivity of blastic plasmacytoid dendritic cell neoplasm to sl 401 an interleukin 3 Receptor targeted biologic agent
    Haematologica, 2015
    Co-Authors: Fanny Angelotdelettre, Arthur E Frankel, Eric K Rowinsky, Anne Roggy, Baptiste Lamarthee, Estelle Seilles, Sabeha Biichle, Bernard Royer, Eric Deconinck, Christopher L Brooks
    Abstract:

    Blastic plasmacytoid dendritic cell neoplasm is an aggressive malignancy derived from plasmacytoid dendritic cells. There is currently no accepted standard of care for treating this neoplasm, and therapeutic strategies have never been prospectively evaluated. Since blastic plasmacytoid dendritic cell neoplasm cells express high levels of Interleukin-3 Receptor α chain (IL3-Rα or CD123), antitumor effects of the Interleukin-3 Receptor-targeted drug SL-401 against blastic plasmacytoid dendritic cell neoplasm were evaluated in vitro and in vivo. The cytotoxicity of SL-401 was assessed in patient-derived blastic plasmacytoid dendritic cell neoplasm cell lines (CAL-1 and GEN2.2) and in primary blastic plasmacytoid dendritic cell neoplasm cells isolated from 12 patients using flow cytometry and an in vitro cytotoxicity assay. The cytotoxic effects of SL-401 were compared to those of several relevant cytotoxic agents. SL-401 exhibited a robust cytotoxicity against blastic plasmacytoid dendritic cell neoplasm cells in a dose-dependent manner. Additionally, the cytotoxic effects of SL-401 were observed at substantially lower concentrations than those achieved in clinical trials to date. Survival of mice inoculated with a blastic plasmacytoid dendritic cell neoplasm cell line and treated with a single cycle of SL-401 was significantly longer than that of untreated controls (median survival, 58 versus 17 days, P<0.001). These findings indicate that blastic plasmacytoid dendritic cell neoplasm cells are highly sensitive to SL-401, and support further evaluation of SL-401 in patients suffering from blastic plasmacytoid dendritic cell neoplasm.

  • sl 401 a novel targeted therapy directed to the interleukin 3 Receptor il 3r blocks plasmacytoid dendritic cell pdc triggered myeloma cell growth and prevents osteoclastogenesis
    Blood, 2014
    Co-Authors: Durgadevi Ravillah, Christopher Brooks, Vincent Macri, Eric K Rowinsky, Yan Song, Paul G Richardson, Dharminder Chauhan, Kenneth C Anderson
    Abstract:

    Introduction Despite the advent of novel therapies, relapse of multiple myeloma (MM) is common and the disease remains largely incurable. Our previous studies showed that bone marrow (BM) plasmacytoid dendritic cells (pDCs) play a central role in the immune deficiency characteristic of MM; as well as promote MM cell growth, survival, and drug resistance (Chauhan et al., Cancer Cell 2009, 16:309-323). These findings identify an integral role of pDCs in MM pathogenesis and provide the basis for targeting pDC-MM interactions as a novel therapeutic strategy in MM. In this context, we found that pDCs exhibit a high level of Interleukin-3 Receptor (IL-3Rα) expression, and pDC-MM interactions trigger secretion of Interleukin-3 (IL-3), which in turn, induces MM cell growth and pDC survival, and promotes osteolytic bone disease in MM. These findings identified targeting IL-3R expressed on pDCs as a promising novel therapeutic strategy. Additionally, our preliminary data show that a significant number of clonogenic side population cells in MM (MM-SPs) with characteristic stem cell like features express IL-3R. Here we examined the effect of SL-401, a novel targeted therapy directed against IL-3R, on pDC-induced MM cell growth, osteoclast (OCL) formation, and MM-SPs. Methods: Patient MM cells, pDCs, and MNCs were obtained from normal donors or MM patients. Cell growth/viability was analyzed using MTT/WST assays. OCL function and bone resorption were measured using the OsteoAssays and TRAP staining. RPMI-8226 cell line was used to isolate MM-SPs by flow-cytometry based Hoechst 33342 staining. SL-401 is a recombinant protein expressed in E. coli. The hybrid gene is comprised of human IL-3 fused to truncated diphtheria toxin (DT). The IL-3 domain of SL-401, which replaces the binding domain of DT, targets SL-401 to cells that overexpress IL-3R. SL-401 was obtained from Stemline Therapeutics, NY; bortezomib, lenalidomide, pomalidomide, and melphalan were purchased from Selleck chemicals, USA. Results: SL-401 decreased the viability of pDCs even at low concentrations (IC50: 0.83 ng/ml; 14.6 pM, p Conclusions: Our preclinical study provides the basis for using SL-401 to directly target pDCs and inhibit the pDC-MM interactions, as well as target osteolytic bone disease and clonogenic side populations, in novel therapeutic strategies to enhance MM cytotoxicity, overcome drug-resistance, and improve patient outcome. Disclosures Macri:Stemline Therapeutics, Inc., New York, NY USA: Employment. Brooks:Stemline Therapeutics: Employment, Equity Ownership. Rowinsky:Stemline Therapeutics: Employment, Equity Ownership. Chauhan:Stemline Therapeutics: Consultancy. Anderson:BMS: Consultancy; Sanofi Aventis: Consultancy; Gilead: Consultancy; Onyx: Consultancy; Millenium: Consultancy; Celgene: Consultancy; Oncopep/Acetylon: Equity Ownership.

  • sl 401 and sl 501 targeted therapeutics directed at the interleukin 3 Receptor inhibit the growth of leukaemic cells and stem cells in advanced phase chronic myeloid leukaemia
    British Journal of Haematology, 2014
    Co-Authors: Olga Frolova, Christopher L Brooks, Eric K Rowinsky, Juliana Benito, Rui Yu Wang, Borys Korchin, Jorge E Cortes, Hagop M Kantarjian, Michael Andreeff, Arthur E Frankel
    Abstract:

    While imatinib and other tyrosine kinase inhibitors (TKIs) are highly efficacious in the treatment of chronic myeloid leukaemia (CML), some patients become refractory to these therapies. After confirming that Interleukin-3 Receptor (IL3R, CD123) is highly expressed on CD34(+) /CD38(-) BCR-ABL1(+) CML stem cells, we investigated whether targeting IL3R with diphtheria toxin (DT)-IL3 fusion proteins SL-401 (DT388 -IL3) and SL-501 (DT388 -IL3[K116W]) could eradicate these stem cells. SL-401 and SL-501 inhibited cell growth and induced apoptosis in the KBM5 cell line and its TKI-resistant KBM5-STI subline. Combinations of imatinib with these agents increased apoptosis in KBM5 and in primary CML cells. In six primary CML samples, including CML cells harbouring the ABL1 T315I mutation, SL-401 and SL-501 decreased the absolute numbers of viable CD34(+) /CD38(-) /CD123(+) CML progenitor cells by inducing apoptosis. IL3-targeting agents reduced clonogenic growth and diminished the fraction of primitive long-term culture-initiating cells in samples from patients with advanced phase CML that were resistant to TKIs or harboured an ABL1 mutation. Survival was also extended in a mouse model of primary TKI-resistant CML blast crisis. These data suggest that the DT-IL3 fusion proteins, SL-401 and SL-501, deplete CML stem cells and may increase the effectiveness of current CML treatment, which principally targets tumour bulk.

  • effect of a novel agent sl 401 targeting interleukin 3 Receptor il 3r on plasmacytoid dendritic cell pdc induced myeloma cell growth and osteolytic bone disease
    Journal of Clinical Oncology, 2014
    Co-Authors: Dharminder Chauhan, Christopher Brooks, Vincent Macri, Eric K Rowinsky, Paul G Richardson, Arghya Ray, Deepika Sharma Das, Kenneth C Anderson
    Abstract:

    8599 Background: Multiple myeloma (MM) remains incurable despite novel therapies, highlighting the need for further identification of factors mediating disease progression and resistance. We showed...

Christopher L Brooks - One of the best experts on this subject based on the ideXlab platform.

  • dna methyltransferase inhibition overcomes diphthamide pathway deficiencies underlying cd123 targeted treatment resistance
    Journal of Clinical Investigation, 2019
    Co-Authors: Katsuhiro Togami, Ross W B Lindsay, Christopher L Brooks, Timothy Pastika, Jason Stephansky, Mahmoud Ghandi, Amanda L Christie, Kristen Jones, Carl Johnson, Anthony Letai
    Abstract:

    The Interleukin-3 Receptor α subunit, CD123, is expressed in many hematologic malignancies including acute myeloid leukemia (AML) and blastic plasmacytoid dendritic cell neoplasm (BPDCN). Tagraxofusp (SL-401) is a CD123-targeted therapy consisting of Interleukin-3 fused to a truncated diphtheria toxin payload. Factors influencing response to tagraxofusp other than CD123 expression are largely unknown. We interrogated tagraxofusp resistance in patients and experimental models and found that it was not associated with CD123 loss. Rather, resistant AML and BPDCN cells frequently acquired deficiencies in the diphthamide synthesis pathway, impairing tagraxofusp's ability to ADP-ribosylate cellular targets. Expression of DPH1, encoding a diphthamide pathway enzyme, was reduced by DNA CpG methylation in resistant cells. Treatment with the DNA methyltransferase inhibitor azacitidine restored DPH1 expression and tagraxofusp sensitivity. We also developed a drug-dependent ADP-ribosylation assay in primary cells that correlated with tagraxofusp activity and may represent an additional novel biomarker. As predicted by these results and our observation that resistance also increased mitochondrial apoptotic priming, we found that the combination of tagraxofusp and azacitidine was effective in patient-derived xenografts treated in vivo. These data have important implications for clinical use of tagraxofusp and led to a phase 1 study combining tagraxofusp and azacitidine in myeloid malignancies.

  • sl 401 a targeted therapy directed to the interleukin 3 Receptor cd123 and sl 801 a reversible inhibitor of exportin 1 xpo1 display synergistic anti tumor activity against hematologic malignancies in vitro
    Blood, 2016
    Co-Authors: John Gionco, Janice Chen, Ross W B Lindsay, Vince Macri, Christopher L Brooks
    Abstract:

    Background: Novel combination therapies have shown success in combating tumor heterogeneity and drug resistance. SL-401 is a targeted therapy directed to the Interleukin-3 Receptor (CD123), which is overexpressed on numerous hematologic malignancies. SL-401 has demonstrated high single agent response rates in an ongoing Phase 2 trial of blastic plasmacytoid dendritic cell neoplasm (BPDCN) and is also being evaluated in the clinic for additional cancers, including acute myeloid leukemia (AML) and myeloproliferative neoplasms (MPNs) as a single agent, and multiple myeloma (MM) in combination with other agents. While SL-401 has demonstrated robust single agent clinical activity in patients with BPDCN, its unique mechanism of action and non-overlapping side effect profile with other agents may lend itself to combination therapy as well. Another class of drugs that has demonstrated clinical activity against several hematologic and solid malignancies is Exportin-1 (XPO1) inhibitors. SL-801 is a novel oral small molecule that reversibly inhibits XPO1 and has shown potent in vitro and in vivo anti-tumor activity against a broad range of hematologic and solid malignancies. SL-801 is currently being evaluated in a Phase 1 trial of patients with advanced solid tumors, and a Phase 1 trial in advanced hematologic cancers is planned. Here, we investigated the in vitro effect of combination treatment of SL-401 and SL-801 against cell lines of chronic myeloid leukemia (CML), AML, MM, and Hodgkin9s lymphoma (HL). Methods: The human K562 CML cell line, MV4-11 AML cell line, RPMI-8226 MM cell line, and L-428 HL cell line were treated with varying concentrations of SL-401 and SL-801 alone or in combination for 48 hours. Cell viability was assessed by the CellTiter Glo in vitro cytotoxicity assay. Combination index (CI) values were calculated using CompuSyn software by the method of Chou and Talalay, and treatment was considered to be synergistic when CI Results: As single agents, SL-401 and SL-801 demonstrated anti-tumor activity in all four cell lines tested. MV4-11 cells were the most sensitive to both drugs, with an IC50 of 34 pM for SL-401 and 21 nM for SL-801. In the other cell lines, the IC50s for SL-401 were 17 nM in K562 cells, 25 nM in RPMI-8226 cells, and 100 nM in L-428 cells, and the IC50s for SL-801 were 99 nM in K562 cells, 51 nM in RPMI-8226 cells, and 494 nM in L-428 cells. When combined with each other, SL-401 and SL-801 potently inhibited cell growth in all cell lines, and CI calculations indicated that the interaction between the two drugs was synergistic at most dose combinations. Notably, CI values Conclusion: These findings demonstrate that SL-401 and SL-801, when combined, act synergistically in their in vitro anti-tumor activity against CML, AML, MM, and HL cells. Investigations into the molecular mechanisms underlying the observed synergy are in progress. These promising results provide rationale for further development of SL-401 and SL-801 combination therapy in the treatment of a broad range of hematologic malignancies. Disclosures Gionco:Stemline Therapeutics, Inc.: Employment. Chen:Stemline Therapeutics, Inc.: Employment, Equity Ownership. Lindsay:Stemline Therapeutics, Inc.: Employment, Equity Ownership. Macri:Stemline Therapeutics, Inc.: Employment, Equity Ownership. Brooks:Stemline Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties.

  • results from ongoing phase 1 2 trial of sl 401 in combination with pomalidomide and dexamethasone in relapsed or refractory multiple myeloma
    Blood, 2016
    Co-Authors: Myo Htut, Janice Chen, Christopher L Brooks, Dharminder Chauhan, Shay Shemesh, Cristina Gasparetto, Jeffrey A Zonder, Thomas G Martin, Emma C Scott, Kenneth C Anderson
    Abstract:

    Background: The bone marrow microenvironment of many multiple myeloma (MM) patients harbors high quantities of plasmacytoid dendritic cells (pDCs), which are specialized immune cells that express the Interleukin-3 Receptor (CD123). These pDCs have been shown to augment MM growth and contribute to drug resistance, suggesting that targeting pDCs may offer clinical benefit for MM patients. SL-401, a novel targeted therapy directed to CD123, has previously demonstrated potent preclinical in vitro and in vivo activity against MM cell lines and primary tumor samples via both a direct anti-MM effect and an indirect effect by targeting neighboring pDCs. SL-401 has also demonstrated synergy in these systems when used in combination with traditional MM therapies including pomalidomide (POM). Clinically, SL-401 has demonstrated high levels of anti-tumor activity in patients with an aggressive CD123+ malignancy of pDC origin, namely blastic plasmacytoid dendritic cell neoplasm (BPDCN). SL-401 is currently being evaluated in combination with POM and dexamethasone (DEX) in relapsed or refractory (r/r) MM patients. Preliminary results are reported here. Methods and Results: This multicenter, single arm Phase 1/2 trial of patients with r/r MM includes a lead-in (stage 1) and expansion (stage 2). In stage 1, patients receive SL-401 as a daily IV infusion at 7, 9, or 12 ug/kg/day 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+DEX in cycles 1 and beyond, in a 3x3 design. In stage 2, patients receive SL-401 in combination with POM+DEX at the dose and regimen determined in stage 1. Objectives include characterization of the safety profile of SL-401 in combination with POM+DEX, including determination of the maximum tolerated or tested dose, and detection of efficacy signals including evaluation of tumor response based on International Myeloma Working Group criteria, duration of response, progression-free survival, and translational evaluation of changes in BM microenvironmental pDCs. As of 7-25-16, 2 patients with r/r MM received SL-401 at 7 ug/kg in combination with POM+DEX. The median age was 65 years (range: 63-67 years). The most common treatment-related AEs, all grades, were thrombocytopenia (2/2, both grade 1) and hypoalbuminemia (2/2, both grade 2); there has been no DLT. Rapid onset decrease in a set of myeloma-related laboratory values from pre-SL-401 treatment was observed in both patients after the first combination cycle of SL-401 and POM+DEX. In one patient, serum M-protein decreased from 2.34 to 1.19 g/dL (cycle 1), free light chain kappa decreased from 40.1 to 8.27 mg/dL (cycle 1), and free light chain kappa/lambda ratio decreased from 58.12 to 41.35 (cycle 1). In the other patient, serum M-protein decreased from 1.88 to 0.87 (cycle 1) and then was 0.96 (cycle 3) g/dL, free light chain kappa decreased from 134 to 49.4 (cycle 1) and then was 92.5 (cycle 3) mg/dL, and free light chain kappa/lambda ratio decreased from 638.1 to 76 (cycle 1) and then was 111.45 (cycle 3). Both patients remain on study receiving ongoing SL-401 at 2+ and 4+ months. Dose escalation to 9 ug/kg is planned if a third patient clears the 7 ug/kg cohort. Conclusions:This is the first clinical study to evaluate SL-401 in combination with other agents. SL-401 thus far has been well-tolerated in combination with POM+DEX in r/r MM patients, with no unexpected AEs observed. After the first cycle of SL-401 and POM+DEX combination therapy, 2 of 2 patients experienced a rapid decrease in serum M-protein and remain on SL-401 therapy. Given CD123 expression on microenvironmental immune pDCs and the potential synergy of SL-401 with certain current MM agents including POM, SL-401 may offer a novel therapeutic approach in MM. This Phase 1/2 trial continues to enroll and updated data will be presented. Clinical trial information: NCT02661022. Disclosures Zonder:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria; Prothena: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Pharmacyclics: Other: DSMC membership. Martin:Sanofi: Research Funding; Amgen: Research Funding. Chen:Stemline Therapeutics, Inc.: Employment, Equity Ownership. Shemesh:Stemline Therapeutics: Employment, Equity Ownership. Brooks:Stemline Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties. Chauhan:Stemline Therapeutics: Consultancy. Anderson:Oncopep: Other: Scientific Founder; Acetylon: Other: Scientific Founder; Gilead: Membership on an entity9s Board of Directors or advisory committees; Celgene: Membership on an entity9s Board of Directors or advisory committees; Sonofi Aventis: Membership on an entity9s Board of Directors or advisory committees; Onyx: Membership on an entity9s Board of Directors or advisory committees. Richardson:Jazz Pharmaceuticals: Consultancy, Membership on an entity9s Board of Directors or advisory committees.

  • in vivo and in vitro sensitivity of blastic plasmacytoid dendritic cell neoplasm to sl 401 an interleukin 3 Receptor targeted biologic agent
    Haematologica, 2015
    Co-Authors: Fanny Angelotdelettre, Arthur E Frankel, Eric K Rowinsky, Anne Roggy, Baptiste Lamarthee, Estelle Seilles, Sabeha Biichle, Bernard Royer, Eric Deconinck, Christopher L Brooks
    Abstract:

    Blastic plasmacytoid dendritic cell neoplasm is an aggressive malignancy derived from plasmacytoid dendritic cells. There is currently no accepted standard of care for treating this neoplasm, and therapeutic strategies have never been prospectively evaluated. Since blastic plasmacytoid dendritic cell neoplasm cells express high levels of Interleukin-3 Receptor α chain (IL3-Rα or CD123), antitumor effects of the Interleukin-3 Receptor-targeted drug SL-401 against blastic plasmacytoid dendritic cell neoplasm were evaluated in vitro and in vivo. The cytotoxicity of SL-401 was assessed in patient-derived blastic plasmacytoid dendritic cell neoplasm cell lines (CAL-1 and GEN2.2) and in primary blastic plasmacytoid dendritic cell neoplasm cells isolated from 12 patients using flow cytometry and an in vitro cytotoxicity assay. The cytotoxic effects of SL-401 were compared to those of several relevant cytotoxic agents. SL-401 exhibited a robust cytotoxicity against blastic plasmacytoid dendritic cell neoplasm cells in a dose-dependent manner. Additionally, the cytotoxic effects of SL-401 were observed at substantially lower concentrations than those achieved in clinical trials to date. Survival of mice inoculated with a blastic plasmacytoid dendritic cell neoplasm cell line and treated with a single cycle of SL-401 was significantly longer than that of untreated controls (median survival, 58 versus 17 days, P<0.001). These findings indicate that blastic plasmacytoid dendritic cell neoplasm cells are highly sensitive to SL-401, and support further evaluation of SL-401 in patients suffering from blastic plasmacytoid dendritic cell neoplasm.

  • sl 401 and sl 501 targeted therapeutics directed at the interleukin 3 Receptor inhibit the growth of leukaemic cells and stem cells in advanced phase chronic myeloid leukaemia
    British Journal of Haematology, 2014
    Co-Authors: Olga Frolova, Christopher L Brooks, Eric K Rowinsky, Juliana Benito, Rui Yu Wang, Borys Korchin, Jorge E Cortes, Hagop M Kantarjian, Michael Andreeff, Arthur E Frankel
    Abstract:

    While imatinib and other tyrosine kinase inhibitors (TKIs) are highly efficacious in the treatment of chronic myeloid leukaemia (CML), some patients become refractory to these therapies. After confirming that Interleukin-3 Receptor (IL3R, CD123) is highly expressed on CD34(+) /CD38(-) BCR-ABL1(+) CML stem cells, we investigated whether targeting IL3R with diphtheria toxin (DT)-IL3 fusion proteins SL-401 (DT388 -IL3) and SL-501 (DT388 -IL3[K116W]) could eradicate these stem cells. SL-401 and SL-501 inhibited cell growth and induced apoptosis in the KBM5 cell line and its TKI-resistant KBM5-STI subline. Combinations of imatinib with these agents increased apoptosis in KBM5 and in primary CML cells. In six primary CML samples, including CML cells harbouring the ABL1 T315I mutation, SL-401 and SL-501 decreased the absolute numbers of viable CD34(+) /CD38(-) /CD123(+) CML progenitor cells by inducing apoptosis. IL3-targeting agents reduced clonogenic growth and diminished the fraction of primitive long-term culture-initiating cells in samples from patients with advanced phase CML that were resistant to TKIs or harboured an ABL1 mutation. Survival was also extended in a mouse model of primary TKI-resistant CML blast crisis. These data suggest that the DT-IL3 fusion proteins, SL-401 and SL-501, deplete CML stem cells and may increase the effectiveness of current CML treatment, which principally targets tumour bulk.

Naveen Pemmaraju - One of the best experts on this subject based on the ideXlab platform.

  • tagraxofusp the first cd123 targeted therapy and first targeted treatment for blastic plasmacytoid dendritic cell neoplasm
    Expert Review of Clinical Pharmacology, 2019
    Co-Authors: Minas P Economides, Andrew A Lane, Deborah Mccue, Naveen Pemmaraju
    Abstract:

    Introduction: CD123 or interleukin 3 Receptor alpha is overexpressed in multiple hematologic malignancies. Tagraxofusp is an intravenously administered CD123-directed cytotoxin consisting of the fusion of Interleukin-3 with a truncated diphtheria toxin payload and was recently approved by the Food and Drug Administration for the treatment of adults and children aged 2 and older with blastic plasmacytoid dendritic cell neoplasm (BPDCN). Areas Covered: In this review, we discuss the use of tagraxofusp in BPDCN, and active clinical trials involving this agent in several hematologic malignancies are also presented. Tagraxofusp has significant efficacy in patients with BPDCN and manageable safety profile, with the most commonly reported adverse events being asymptomatic elevation of alanine and aspartate aminotransferase levels, hypoalbuminemia, peripheral edema, and thrombocytopenia. The most serious side effect is capillary leak syndrome that can be lethal in some cases but the risk may be mitigated by early recognition and intervention. Expert Opinion: Tagraxofusp has been introduced as a novel treatment of BPDCN, a rare hematologic malignancy, for which no standard therapy previously existed. Many patients treated with this agent were able to be bridged to stem cell transplantation, including older patients. In the future, combinations of tagraxofusp with other targeted agents will be explored.

  • results of pivotal phase 2 clinical trial of tagraxofusp sl 401 in patients with blastic plasmacytoid dendritic cell neoplasm bpdcn
    Blood, 2018
    Co-Authors: Naveen Pemmaraju, Kendra L Sweet, Andrew A Lane, Anthony S Stein, Sumithira Vasu, William Blum, David A Rizzieri, Eunice S Wang, Madeleine Duvic, Sharon Spence
    Abstract:

    Background: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a highly aggressive hematologic malignancy with a historical overall survival (OS) of ~8-14 months from diagnosis and no approved therapies or standard of care. Tagraxofusp (Elzonris™; SL-401) is a novel targeted therapy directed to the Interleukin-3 Receptor-α (CD123), a target expressed on BPDCN and other malignancies. Tagraxofusp was granted Breakthrough Therapy Designation for the treatment of patients with BPDCN, and a rolling Biologics License Application (BLA) submission to the U.S. Food and Drug Administration (FDA) was completed in June 2018. Detailed results from the pivotal trial of tagraxofusp in BPDCN will be presented. Methods: This pivotal Phase 2 clinical trial is a multicenter, open label, non-randomized, single-arm trial designed to determine safety and efficacy of tagraxofusp in patients with BPDCN. In Stage 1 (lead-in), first line (1L) and relapsed/refractory (r/r) patients with BPDCN received tagraxofusp as a daily IV infusion at 7, 9, or 12 mcg/kg/day on days 1-5 of a 21-day cycle. Patients with BPDCN enrolled in subsequent stages received tagraxofusp at the dose determined in Stage 1 (12 mcg/kg). Stage 2 (expansion) enrolled 1L and r/r patients, and Stage 3 (pivotal, confirmatory) enrolled only 1L patients. Results: 45 patients with BPDCN (Stages 1 and 2, n=32; Stage 3, n=13) were enrolled at 7 sites in the US, including 32 (71%) patients as 1L. Median age was 70 years (range, 22-84); 82% male. Median follow-up for all 1L patients treated at 12 mcg/kg (n=29) was 13.8 months (range 0.2-37.4+). The most common treatment-related adverse events (TRAEs) at 12 mcg/kg in 148 patients treated in four clinical trials with tagraxofusp were transaminitis (44%), hypoalbuminemia (44%), and thrombocytopenia (26%). Capillary leak syndrome (CLS), all grades, occurred in 17% of patients across all indications at 12 mcg/kg; 0.7% (1/148) and 1.6% (3/182) of cases resulted in death across all indications at 12 mcg/kg and all doses, respectively. The Stage 3 pivotal cohort met its primary endpoint with a 54% (7/13) rate of CR+CRc (95% CI: 25.1, 80.8). Across Stages 1, 2 and 3, in 1L patients dosed at 12 mcg/kg (n=29), ORR was 90% (26/29) with a 72% (21/29) rate of CR+CRc+CRi (ORR=overall response rate; CR=complete response; CRc=clinical CR: absence of gross disease with minimal residual skin abnormality; CRi=CR with incomplete hematologic recovery). 45% (13/29) of first-line patients treated with 12 mcg/kg were bridged to stem cell transplant (SCT) (10 allo+3 auto). In r/r patients, ORR was 69% (9/13) with a 38% (5/13) rate of CR+CRc+CRi. Additional patient follow-up will be provided. Conclusions: The pivotal trial of tagraxofusp was the largest prospectively designed, multi-center trial specifically dedicated to patients with BPDCN. This study has met its primary endpoint, and also demonstrated high response rates that were generally achieved early in the course of treatment and maintained over multiple cycles of therapy. Safety profile demonstrated most common toxicities of transaminitis, hypoalbuminemia, and thrombocytopenia; occurrence of CLS was the most serious TRAE, which was overall manageable in this population. Patients with BPDCN are being enrolled in an additional cohort, Stage 4, to ensure ongoing access. Tagraxofusp is also being evaluated in other trials including in patients with chronic myelomonocytic leukemia (CMML) and myelofibrosis (MF). Disclosures Pemmaraju: celgene: Consultancy, Honoraria; SagerStrong Foundation: Research Funding; stemline: Consultancy, Honoraria, Research Funding; cellectis: Research Funding; novartis: Research Funding; abbvie: Research Funding; samus: Research Funding; daiichi sankyo: Research Funding; plexxikon: Research Funding; Affymetrix: Research Funding. Lane: N-of-one: Consultancy; Stemline Therapeutics: Research Funding. Sweet: Agios: Consultancy; Jazz: Speakers Bureau; BMS: Honoraria; Novartis: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Astellas: Consultancy; Celgene: Honoraria, Speakers Bureau; Jazz: Speakers Bureau; Astellas: Consultancy; BMS: Honoraria; Phizer: Consultancy; Agios: Consultancy; Celgene: Honoraria, Speakers Bureau; Phizer: Consultancy. Stein: Amgen Inc.: Speakers Bureau; Celgene: Speakers Bureau. Vasu: Boehringer Ingelheim Inc: Membership on an entity9s Board of Directors or advisory committees. Blum: Tolero: Research Funding; Forma: Research Funding; Astellas: Consultancy; Xencor: Research Funding; Boehringer Ingelheim: Research Funding; Pfizer: Consultancy. Rizzieri: Gilead: Consultancy, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Arog: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Novartis: Consultancy; Teva: Consultancy, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Jazz: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity9s Board of Directors or advisory committees. Wang: Pfizer: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Jazz: Speakers Bureau; Novartis: Speakers Bureau; Novartis: Speakers Bureau; Jazz: Speakers Bureau; Abbvie: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Amgen: Consultancy; Pfizer: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Amgen: Consultancy; Abbvie: Consultancy, Membership on an entity9s Board of Directors or advisory committees. Duvic: Guidepoint Global: Consultancy; Eisai: Research Funding; Allos: Research Funding; Clinical Care Options: Consultancy; Array Biopharma: Consultancy, Honoraria; Spatz Foundation: Research Funding; Defined Health: Consultancy; Medivir AB: Membership on an entity9s Board of Directors or advisory committees; MiRagen Therapeutics: Consultancy; MEDACorp: Consultancy; Taiwan Liposome Company LTD: Consultancy; Medscape: Other: Speaker/PReceptor; Concert Pharmaceuticals, Inc.: Consultancy; Kyowa Hakko Kirin, Co: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Huya Bioscience Int9l: Consultancy; Shape: Research Funding; Kiniksa Pharmaceuticals: Consultancy; Soligenix, Inc.: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Forty Seven, Inc.: Membership on an entity9s Board of Directors or advisory committees; Celgene Corp: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees; Cell Medica Inc.: Consultancy, Honoraria; Dr. Reddy9s Laboratories (A.K.A. Promius Pharma): Consultancy; Huron Consulting Group: Consultancy; Aclaris Therapeutics Int9l Ltd.: Honoraria, Membership on an entity9s Board of Directors or advisory committees; UT MD Anderson Cancer Center: Employment; The Lynx Group: Consultancy; Evidera, Inc.: Consultancy; Mallinckrddt Pharmaceuticals (formerly Therakos): Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; American Council on Extracorporeal Photopheresis (ACE): Membership on an entity9s Board of Directors or advisory committees; Millennium Pharmaceuticals, Inc.: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Tetralogics: Research Funding; Precision Oncology, LLC: Membership on an entity9s Board of Directors or advisory committees; Oncoceuticals: Research Funding; Jonathan Wood & Associates: Other: Speaker; Seattle Genetics: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Rhizen Pharma: Research Funding. Spence: Stemline Therapeutics: Consultancy. Shemesh: Stemline Therapeutics: Employment, Equity Ownership. Brooks: Stemline Therapeutics: Employment, Equity Ownership. Bergstein: Stemline Therapeutics: Employment, Equity Ownership. Chen: Stemline Therapeutics: Employment, Equity Ownership. Dunn: Stemline Therapeutics: Employment, Equity Ownership. McDonald: Stemline Therapeutics: Employment, Equity Ownership. Sloan: Stemline Therapeutics: Consultancy. Konopleva: Stemline Therapeutics: Research Funding.

  • results of pivotal phase 2 trial of sl 401 in patients with blastic plasmacytoid dendritic cell neoplasm bpdcn
    Blood, 2017
    Co-Authors: Naveen Pemmaraju, Kendra L Sweet, Andrew A Lane, Anthony S Stein, Sumithira Vasu, William Blum, David A Rizzieri, Eunice S Wang, Madeleine Duvic, Phyu P Aung
    Abstract:

    Abstract Background SL-401 is a novel targeted therapy, comprised of recombinant IL-3 genetically fused to a truncated diphtheria toxin payload, directed to the Interleukin-3 Receptor α (CD123), a target highly expressed on blastic plasmacytoid dendritic cell neoplasm (BPDCN). SL-401 has been granted breakthrough therapy designation (BTD) for the treatment of patients with BPDCN. BPDCN is an aggressive hematologic malignancy with poor outcomes, including ~12 month overall survival (OS) from diagnosis, and no approved therapies or standard of care, highlighting the need for novel therapeutic approaches. Detailed results from the pivotal Phase 2 trial of SL-401 in BPDCN will be presented for the first time. Methods This pivotal Phase 2 trial of SL-401 is a multicenter, open label, non-randomized, single-arm trial. In Stage 1, first line (1L) and relapsed/refractory (r/r) BPDCN patients received SL-401 as a daily IV infusion at 7, 9, or 12 mcg/kg/day on days 1-5 of a 21-day cycle. Patients with BPDCN enrolled in subsequent stages received SL-401 at the dose determined in Stage 1 (12mcg/kg). Stage 2 enrolled 1L and r/r BPDCN patients, and Stage 3 enrolled only 1L BPDCN patients. Stage 3 was prospectively designed with a pre-specified analysis plan to support potential registration. Enrollment in Stages 1-3 has been completed. To ensure ongoing patient access, a Stage 4 cohort is currently open for enrollment of both 1L and r/r BPDCN patients. Results 45 patients with BPDCN (Stages 1 and 2: n=32; Stage 3: n=13) were enrolled at 7 sites in the US. The following results are from Stages 1 and 2; Stage 3 data will be presented at the conference. Median age was 72 years (range, 29-85 years); 81% were male. In Stage 1, 12 mcg/kg was the highest tested dose for BPDCN; MTD was not reached. Across all patients and doses, there was an 84% (27/32) overall response rate (ORR), and 59% (19/32) rate of complete response (CR), which includes CR with incomplete hematologic recovery (CRi) (n=1) and clinical CR (CRc; CR with minimal residual skin abnormality) (n=4). ORR was 95% (18/19), with a CR rate of 79% (15/19), in 1L patients. In r/r patients, ORR was 69% (9/13) with a 31% (4/13) CR rate. Eight patients with BPDCN (28%: 8/29) were bridged to stem cell transplant (SCT) following remission with SL-401 (12 mcg/kg), including 1 r/r patient; no cases of post-SCT veno-occlusive disease (VOD) have been reported in these patients. In first-line patients (SL-401: 12 mcg/kg), median OS has not been reached; PFS: 9.5 months. In r/r patients, median OS was 8.5 months; PFS: 3.6 months. Median follow-up was 4.5 months (range 0.5 to 22.9). The most common treatment-related adverse events (TRAEs) with SL-401 across BPDCN and other indications (acute myeloid leukemia (AML), myeloproliferative neoplasms (MPN), and multiple myeloma) (n=134 patients) were hypoalbuminemia (43%), transaminitis (43%), and thrombocytopenia (26%). Capillary leak syndrome (CLS), a well-documented side effect, occurred in 18% (24/134) of patients, and has been generally manageable and reversible; 2.2% (3/134) of cases resulted in deaths. Conclusions SL-401 continues to demonstrate notable single agent activity, including multiple CRs, in Stages 1 and 2 of the pivotal Phase 2 BPDCN trial. In 1L patients (SL-401: 12 mcg/kg), 44% (7/16) were bridged to SCT after a durable response from SL-401, and median OS has not been reached. SL-401 side effect profile has remained generally consistent and manageable over increased patient exposure and experience. Analysis of Stage 3 data is ongoing and detailed pivotal efficacy data from this cohort, along with updated Stage 1 and 2 results, will be presented at the conference for the first time. Disclosures Pemmaraju: LFB: Consultancy, Honoraria; Incyte Corporation: Consultancy, Honoraria; stemline: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Honoraria, Research Funding; cellectis: Research Funding; affymetrix: Research Funding; roche diagnostics: Consultancy, Honoraria; abbvie: Research Funding. Lane: Stemline Therapeutics: Research Funding; N-of-one: Consultancy. Stein: Stemline: Consultancy; Amgen: Consultancy, Speakers Bureau. Vasu: Stemline Therapeutics: Research Funding; Boehringer-Ingelheim: Research Funding. Rizzieri: Erytech: Research Funding; Shire: Research Funding. Duvic: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Membership on an entity's Board of Directors or advisory committees, Other: Research funding (paid to institution); . Shubert: Stemline Therapeutics: Employment. Spence: Stemline Therapeutics: Consultancy. Shemesh: Stemline Therapeutics: Employment. Chen: Stemline Therapeutics: Employment. Brooks: Stemline Therapeutics: Employment, Equity Ownership, Patents & Royalties. Bergstein: Stemline Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. McDonald: Stemline Therapeutics: Employment, Equity Ownership. Goswami: Stemline Therapeutics: Employment. Sloan: Stemline Pharmaceuticals: Consultancy; Molecular Templates, Inc.: Consultancy. Lancet: Biopath, Biosight, Boehringer Ingelheim, Celator/Jazz, Celgene, Janssen, Karyopharm Therapeutics, and Novartis: Consultancy; Pfizer: Other: Institutional research funding. Kantarjian: Pfizer: Research Funding; Amgen: Research Funding; Bristol-Meyers Squibb: Research Funding; ARIAD: Research Funding; Novartis: Research Funding; Delta-Fly Pharma: Research Funding.

  • results from phase 2 trial ongoing expansion stage of sl 401 in patients with blastic plasmacytoid dendritic cell neoplasm bpdcn
    Blood, 2016
    Co-Authors: Naveen Pemmaraju, Kendra L Sweet, Andrew A Lane, Anthony S Stein, Sumithira Vasu, William Blum, David A Rizzieri, Eunice S Wang, Madeleine Duvic, Janice Chen
    Abstract:

    Background: SL-401 is a targeted therapy directed to the Interleukin-3 Receptor (CD123), a target overexpressed on blastic plasmacytoid dendritic cell neoplasm (BPDCN) and other hematologic malignancies. BPDCN is an aggressive hematologic malignancy of unmet medical need that often presents in bone marrow and skin, and may also involve lymph nodes and viscera. Long-term outcomes after treatment with chemotherapy have been very poor, with median overall survival from diagnosis of ~12 months, highlighting the need for novel therapies. Results from the Phase 2 trial of SL-401 in patients with BPDCN are reported here. Methods:This multicenter, single-arm Phase 2 trial of patients with BPDCN includes a lead-in (stage 1) and expansion (stage 2). In stage 1, patients with BPDCN or relapsed or refractory (r/r) AML received SL-401 as a daily IV infusion at 7, 9, 12, or 16 ug/kg/day for days 1-5 of a 21 day cycle. In stage 2, patients with BPDCN receive SL-401 at the dose determined in stage 1. Results: As of 7/25/16, 29 patients with BPDCN have received SL-401, including 16 first-line and 10 relapsed/refractory (r/r) adults and 3 pediatric patients (under compassionate use). The 26 adult patients (9+17 in stages 1&2) received SL-401 at 7 ug/kg (n=3 [stage 1]) or 12 ug/kg (n=23 [6+17 in stages 1&2]). The median adult age was 69 years (range: 29-82 years). In stage 1, 12 ug/kg was the highest tested dose for BPDCN; MTD was not reached in BPDCN. Results in AML (r/r) patients will be reported separately. The most common treatment-related AEs, all grades, were transient transaminase elevation (54%) and hypoalbuminemia (38%). Transient thrombocytopenia was also noted (19%). The most common ≥ Grade 3 treatment-related AEs were transient transaminase elevation (42%) and thrombocytopenia (19%). Two stage 1 patients developed capillary leak syndrome (CLS): gr 5 (7 ug/kg) and gr 4 (12 ug/kg). Safety precautions, including monitoring of albumin levels and body weight, were successfully implemented to minimize risk of severe CLS, which has not occurred in patients with BPDCN since adoption. Twenty-one of 26 adult patients were evaluable for response (response assessment from 3 recently treated patients are pending; 1 patient was discontinued for as yet unspecified reasons; and 1 patient treated at 7 ug/kg was not evaluable for response due to AE); median follow-up for evaluable patients was 6.9 months (range: 0.6-17.6 months). An 86% (18/21) ORR was observed in evaluable adult BPDCN patients. ORR in evaluable patients was 100% (14/14) in first-line and 57% (4/7) in r/r BPDCN. Of these, 92% (11/12) of first-line patients treated at 12 ug/kg had a CR (n=8) or clinical CR (CRc: a CR in non-skin organs with gross reduction in cutaneous lesions and residual microscopic skin disease) (n=3). 75% (9/12) of these patients remain progression free for 3+ to 16+ months (ongoing), including 4 patients who remain on SL-401 in remission (for 3+ to 12+ months [up to 16+ cycles], ongoing) and 5 additional patients who experienced a major response on SL-401 (3 CR, 1 CRc, 1 PR) and were then successfully bridged to stem cell transplant (SCT; 3 auto-SCT and 2 allo-SCT) and all remain progression free for 3+ to 16+months (ongoing) since first SL-401 dose. Notably, a patient with r/r BPDCN was recently bridged to allo-SCT following CRc on SL-401. Conclusions: SL-401 demonstrates robust single agent activity in BPDCN, including 86% ORR in all-lines, with multiple CRs, in evaluable patients. Six patients, including 1 r/r patient, have proceeded to SCT after achieving a major response from SL-401, and an additional 7 patients remain on SL-401 for up to 12+ months, ongoing. The SL-401 side effect profile remains manageable, and no unexpected AEs have emerged with increased treatment duration, drug exposure, and patient enrollment. Response duration, progression-free and overall survival data continue to be encouraging and updated data will be presented. Clinical trial information: NCT02113982. Disclosures Lane:N-of-1: Consultancy; Stemline Therapeutics: Research Funding. Sweet:Ariad: Consultancy, Speakers Bureau; Incyte Corporation: Research Funding; Pfizer: Speakers Bureau; Karyopharm: Honoraria, Research Funding; Novartis: Consultancy, Speakers Bureau. Stein:Seattle Genetics: Research Funding; Amgen: Consultancy, Research Funding, Speakers Bureau; Stemline Therapeutics: Consultancy, Research Funding; Argios: Research Funding; Celgene: Research Funding. Wang:Immunogen: Research Funding; Incyte: Speakers Bureau. Chen:Stemline Therapeutics, Inc.: Employment, Equity Ownership. Shemesh:Stemline Therapeutics: Employment, Equity Ownership. McDonald:Stemline Therapeutics: Employment, Equity Ownership. Brooks:Stemline Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties. Lancet:Quantum First: Consultancy; Pfizer: Research Funding; Seattle Genetics: Consultancy; Novartis: Consultancy; Biopath Holdings: Consultancy; ERYtech: Consultancy; Karyopharm: Consultancy; Baxalta: Consultancy; Kalo Bios: Consultancy; Celgene: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy; Boehringer-Ingelheim: Consultancy; Amgen: Consultancy. Kantarjian:Bristol-Myers Squibb: Research Funding; Amgen: Research Funding; ARIAD: Research Funding; Pfizer Inc: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding. Konopleva:Reata Pharmaceuticals: Equity Ownership; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Stemline: Consultancy, Research Funding; Eli Lilly: Research Funding; Cellectis: Research Funding; Calithera: Research Funding.

  • results from phase 2 registration trial of sl 401 in patients with blastic plasmacytoid dendritic cell neoplasm bpdcn lead in completed expansion stage ongoing
    Journal of Clinical Oncology, 2016
    Co-Authors: Naveen Pemmaraju, Kendra L Sweet, Andrew A Lane, Anthony S Stein, Sumithira Vasu, David A Rizzieri, Eunice S Wang, William G Blum, Madeleine Duvic, Janice Chen
    Abstract:

    7006Background: SL-401 is a targeted therapy directed to the Interleukin-3 Receptor (CD123), a target overexpressed on BPDCN and other hematologic cancers. BPDCN is a rare, aggressive hematologic m...

Kenneth C Anderson - One of the best experts on this subject based on the ideXlab platform.

  • results from ongoing phase 1 2 trial of sl 401 in combination with pomalidomide and dexamethasone in relapsed or refractory multiple myeloma
    Blood, 2016
    Co-Authors: Myo Htut, Janice Chen, Christopher L Brooks, Dharminder Chauhan, Shay Shemesh, Cristina Gasparetto, Jeffrey A Zonder, Thomas G Martin, Emma C Scott, Kenneth C Anderson
    Abstract:

    Background: The bone marrow microenvironment of many multiple myeloma (MM) patients harbors high quantities of plasmacytoid dendritic cells (pDCs), which are specialized immune cells that express the Interleukin-3 Receptor (CD123). These pDCs have been shown to augment MM growth and contribute to drug resistance, suggesting that targeting pDCs may offer clinical benefit for MM patients. SL-401, a novel targeted therapy directed to CD123, has previously demonstrated potent preclinical in vitro and in vivo activity against MM cell lines and primary tumor samples via both a direct anti-MM effect and an indirect effect by targeting neighboring pDCs. SL-401 has also demonstrated synergy in these systems when used in combination with traditional MM therapies including pomalidomide (POM). Clinically, SL-401 has demonstrated high levels of anti-tumor activity in patients with an aggressive CD123+ malignancy of pDC origin, namely blastic plasmacytoid dendritic cell neoplasm (BPDCN). SL-401 is currently being evaluated in combination with POM and dexamethasone (DEX) in relapsed or refractory (r/r) MM patients. Preliminary results are reported here. Methods and Results: This multicenter, single arm Phase 1/2 trial of patients with r/r MM includes a lead-in (stage 1) and expansion (stage 2). In stage 1, patients receive SL-401 as a daily IV infusion at 7, 9, or 12 ug/kg/day 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+DEX in cycles 1 and beyond, in a 3x3 design. In stage 2, patients receive SL-401 in combination with POM+DEX at the dose and regimen determined in stage 1. Objectives include characterization of the safety profile of SL-401 in combination with POM+DEX, including determination of the maximum tolerated or tested dose, and detection of efficacy signals including evaluation of tumor response based on International Myeloma Working Group criteria, duration of response, progression-free survival, and translational evaluation of changes in BM microenvironmental pDCs. As of 7-25-16, 2 patients with r/r MM received SL-401 at 7 ug/kg in combination with POM+DEX. The median age was 65 years (range: 63-67 years). The most common treatment-related AEs, all grades, were thrombocytopenia (2/2, both grade 1) and hypoalbuminemia (2/2, both grade 2); there has been no DLT. Rapid onset decrease in a set of myeloma-related laboratory values from pre-SL-401 treatment was observed in both patients after the first combination cycle of SL-401 and POM+DEX. In one patient, serum M-protein decreased from 2.34 to 1.19 g/dL (cycle 1), free light chain kappa decreased from 40.1 to 8.27 mg/dL (cycle 1), and free light chain kappa/lambda ratio decreased from 58.12 to 41.35 (cycle 1). In the other patient, serum M-protein decreased from 1.88 to 0.87 (cycle 1) and then was 0.96 (cycle 3) g/dL, free light chain kappa decreased from 134 to 49.4 (cycle 1) and then was 92.5 (cycle 3) mg/dL, and free light chain kappa/lambda ratio decreased from 638.1 to 76 (cycle 1) and then was 111.45 (cycle 3). Both patients remain on study receiving ongoing SL-401 at 2+ and 4+ months. Dose escalation to 9 ug/kg is planned if a third patient clears the 7 ug/kg cohort. Conclusions:This is the first clinical study to evaluate SL-401 in combination with other agents. SL-401 thus far has been well-tolerated in combination with POM+DEX in r/r MM patients, with no unexpected AEs observed. After the first cycle of SL-401 and POM+DEX combination therapy, 2 of 2 patients experienced a rapid decrease in serum M-protein and remain on SL-401 therapy. Given CD123 expression on microenvironmental immune pDCs and the potential synergy of SL-401 with certain current MM agents including POM, SL-401 may offer a novel therapeutic approach in MM. This Phase 1/2 trial continues to enroll and updated data will be presented. Clinical trial information: NCT02661022. Disclosures Zonder:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria; Prothena: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Pharmacyclics: Other: DSMC membership. Martin:Sanofi: Research Funding; Amgen: Research Funding. Chen:Stemline Therapeutics, Inc.: Employment, Equity Ownership. Shemesh:Stemline Therapeutics: Employment, Equity Ownership. Brooks:Stemline Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties. Chauhan:Stemline Therapeutics: Consultancy. Anderson:Oncopep: Other: Scientific Founder; Acetylon: Other: Scientific Founder; Gilead: Membership on an entity9s Board of Directors or advisory committees; Celgene: Membership on an entity9s Board of Directors or advisory committees; Sonofi Aventis: Membership on an entity9s Board of Directors or advisory committees; Onyx: Membership on an entity9s Board of Directors or advisory committees. Richardson:Jazz Pharmaceuticals: Consultancy, Membership on an entity9s Board of Directors or advisory committees.

  • sl 401 a novel targeted therapy directed to the interleukin 3 Receptor il 3r blocks plasmacytoid dendritic cell pdc triggered myeloma cell growth and prevents osteoclastogenesis
    Blood, 2014
    Co-Authors: Durgadevi Ravillah, Christopher Brooks, Vincent Macri, Eric K Rowinsky, Yan Song, Paul G Richardson, Dharminder Chauhan, Kenneth C Anderson
    Abstract:

    Introduction Despite the advent of novel therapies, relapse of multiple myeloma (MM) is common and the disease remains largely incurable. Our previous studies showed that bone marrow (BM) plasmacytoid dendritic cells (pDCs) play a central role in the immune deficiency characteristic of MM; as well as promote MM cell growth, survival, and drug resistance (Chauhan et al., Cancer Cell 2009, 16:309-323). These findings identify an integral role of pDCs in MM pathogenesis and provide the basis for targeting pDC-MM interactions as a novel therapeutic strategy in MM. In this context, we found that pDCs exhibit a high level of Interleukin-3 Receptor (IL-3Rα) expression, and pDC-MM interactions trigger secretion of Interleukin-3 (IL-3), which in turn, induces MM cell growth and pDC survival, and promotes osteolytic bone disease in MM. These findings identified targeting IL-3R expressed on pDCs as a promising novel therapeutic strategy. Additionally, our preliminary data show that a significant number of clonogenic side population cells in MM (MM-SPs) with characteristic stem cell like features express IL-3R. Here we examined the effect of SL-401, a novel targeted therapy directed against IL-3R, on pDC-induced MM cell growth, osteoclast (OCL) formation, and MM-SPs. Methods: Patient MM cells, pDCs, and MNCs were obtained from normal donors or MM patients. Cell growth/viability was analyzed using MTT/WST assays. OCL function and bone resorption were measured using the OsteoAssays and TRAP staining. RPMI-8226 cell line was used to isolate MM-SPs by flow-cytometry based Hoechst 33342 staining. SL-401 is a recombinant protein expressed in E. coli. The hybrid gene is comprised of human IL-3 fused to truncated diphtheria toxin (DT). The IL-3 domain of SL-401, which replaces the binding domain of DT, targets SL-401 to cells that overexpress IL-3R. SL-401 was obtained from Stemline Therapeutics, NY; bortezomib, lenalidomide, pomalidomide, and melphalan were purchased from Selleck chemicals, USA. Results: SL-401 decreased the viability of pDCs even at low concentrations (IC50: 0.83 ng/ml; 14.6 pM, p Conclusions: Our preclinical study provides the basis for using SL-401 to directly target pDCs and inhibit the pDC-MM interactions, as well as target osteolytic bone disease and clonogenic side populations, in novel therapeutic strategies to enhance MM cytotoxicity, overcome drug-resistance, and improve patient outcome. Disclosures Macri:Stemline Therapeutics, Inc., New York, NY USA: Employment. Brooks:Stemline Therapeutics: Employment, Equity Ownership. Rowinsky:Stemline Therapeutics: Employment, Equity Ownership. Chauhan:Stemline Therapeutics: Consultancy. Anderson:BMS: Consultancy; Sanofi Aventis: Consultancy; Gilead: Consultancy; Onyx: Consultancy; Millenium: Consultancy; Celgene: Consultancy; Oncopep/Acetylon: Equity Ownership.

  • effect of a novel agent sl 401 targeting interleukin 3 Receptor il 3r on plasmacytoid dendritic cell pdc induced myeloma cell growth and osteolytic bone disease
    Journal of Clinical Oncology, 2014
    Co-Authors: Dharminder Chauhan, Christopher Brooks, Vincent Macri, Eric K Rowinsky, Paul G Richardson, Arghya Ray, Deepika Sharma Das, Kenneth C Anderson
    Abstract:

    8599 Background: Multiple myeloma (MM) remains incurable despite novel therapies, highlighting the need for further identification of factors mediating disease progression and resistance. We showed...

  • sl 401 a novel targeted therapy directed to the interleukin 3 Receptor il 3r inhibits plasmacytoid dendritic cell pdc induced myeloma cell growth and overcomes drug resistance
    Blood, 2013
    Co-Authors: Arghya Ray, Christopher L Brooks, Vincent Macri, Eric K Rowinsky, Paul G Richardson, Dharminder Chauhan, Deepika Sharma Das, Ze Tian, Kenneth C Anderson
    Abstract:

    Introduction Multiple Myeloma (MM) remains incurable despite the advent of novel drugs, highlighting the need for further identification of factors mediating disease progression and resistance. The bone marrow (BM) microenvironment confers growth, survival, and drug resistance in MM cells. Our earlier study using both in vitro and in vivo MM xenograft models showed increased numbers of plasmacytoid dendritic cells (pDCs) in the MM BM, which promote MM cell growth and survival (Chauhan et al., Cancer Cell 2009, 16:309-323) . We found increased IL-3 levels upon pDC-MM interaction, which in turn, trigger MM cell growth and pDC survival. Interestingly, the IL-3 Receptor (IL-3R) is highly expressed on pDCs. In this study, we utilized SL-401, a novel targeted therapy directed to IL-3R, to examine whether blockade of the IL-3-IL3R signaling axis inhibits pDC-induced MM cell growth. Methods To study the anti-MM activity of SL-401, we utilized MM cell lines, patient MM cells, and pDCs from normal healthy donors or MM patients. The pDCs and MM cells were cultured alone or together in the presence or absence of SL-401, and cell growth or viability was analyzed using WST/MTT assays. Results MM cells or pDCs were freshly isolated and treated with various concentrations of SL-401. SL-401 significantly decreased the viability of pDCs even at low concentrations (IC50: 0.83 ng/ml; 14.6 pM) (mean ± SD; n=4, P < 0.005). SL-401 decreased the viability of MM cells at clinically achievable doses, without significantly affecting the viability of normal peripheral blood mononuclear cells. Co-culture of pDCs with MM cells triggered growth of various MM cell lines, which was blocked in the presence of low concentrations of SL-401 (0.8 ng/ml). MM patient-derived pDCs also induced proliferation of MM cell lines and primary MM cells; and importantly, SL-401 inhibited pDC-triggered MM cell growth (P < 0.005). Moreover, 3 of 5 samples were obtained from patients whose disease was progressing while on bortezomib, dexamethasone, and lenalidomide therapies. Moreover, SL-401 blocked pDC-induced growth of dexamethasone-, doxorubicin- or melphalan-resistant MM cell lines (MM.1R, Dox-40 and LR5 cell lines, respectively). Finally, combinations of SL-401 with bortezomib, melphalan, or lenalidomide showed synergistic anti-MM activity. Conclusions Our preclinical study provides the basis for directly targeting pDCs and inhibiting the pDC-MM interaction, as well as targeting MM, in novel therapeutic strategies using SL-401 to enhance MM cytotoxicity, overcome drug-resistance, and improve patient outcome. Disclosures: Macri: Stemline Therapeutics, Inc., New York, NY USA : Employment. Brooks: Stemline Therapeutics, Inc., New York, NY USA : Employment. Rowinsky: Stemline Therapeutics, Inc., New York, NY USA : Employment.