scholarly journals The Fully Human Anti-CD47 Antibody SRF231 Has Dual-Mechanism Antitumor Activity Against Chronic Lymphocytic Leukemia (CLL) Cells and Increases the Activity of Both Rituximab and Venetoclax

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4393-4393 ◽  
Author(s):  
Rebecca Valentin ◽  
Marisa O. Peluso ◽  
Timothy Z. Lehmberg ◽  
Ammar Adam ◽  
Li Zhang ◽  
...  
Keyword(s):  
Cell Death ◽  
Tumor Cell ◽  
Board Of Directors ◽  
Tumor Cells ◽  
Research Funding ◽  
Ex Vivo ◽  
Employment Equity ◽  
Advisory Committees ◽  
Isotype Control ◽  
Equity Ownership

Abstract Background CD47 is over-expressed by many tumor types and protects tumor cells from destruction via tumor-intrinsic and -extrinsic means. The fully human anti-CD47 monoclonal antibody (mAb) SRF231 has previously been shown to block the "don't eat me" CD47/signal regulatory protein alpha (SIRPα) interaction and induce macrophage-mediated phagocytic uptake of CD47-expressing tumor cells, either alone or in the presence of anti-CD20 mAb. Furthermore, SRF231 inhibited tumor growth in preclinical models of aggressive non-Hodgkin lymphoma (Holland P, et al. ASH 2016). Here, we explored the activity of SRF231 against CLL cells for the first time, both as monotherapy and in combination with rituximab or venetoclax (VEN). Methods Peripheral blood mononuclear cells from 24 CLL patients were evaluated for CD47 surface expression by flow cytometry. Primary CLL or Jurkat target cells were treated ex vivo with SRF231 or isotype control and evaluated in phagocytosis and cell death assays. Human monocyte-derived macrophages were cocultured with fluorescently-labeled target tumor cells and exposed to SRF231 and/or rituximab (commercial supply). BH3 profiling was performed by gently permeabilizing primary CLL cells and measuring the release of cytochrome C (Cyto-C) in response to BH3-only peptides by flow cytometry. Priming for apoptosis was measured by Cyto-C release in response to BIM BH3 peptide, and pro-survival protein dependencies were measured by response to specific BH3-only sensitizer peptides. Statistical analyses were by unpaired and paired t-test with a two-tailed nominal p ≤ 0.05 considered as significant. In vivo antitumor activity was assessed using tumor xenograft studies in CB17 SCID mice. Mice with established, subcutaneous Ri-1 tumors were randomized and treated with either isotype control, SRF231, VEN (Medkoo), or combination of SRF231 and VEN. Results CD47 was expressed in all primary CLL cells (n = 24, median mean fluorescence intensity [MFI] 7913, range 3575-18,329) with a slightly higher expression in unmutated CLL (U-CLL) vs mutated CLL (M-CLL) samples (U-CLL median MFI = 9106, n = 8 vs M-CLL, median MFI = 7713, n = 14, 2 unknown, p = 0.047). Primary CLL cells were significantly more susceptible to phagocytosis upon ex vivo treatment with SRF231 in combination with rituximab (median % increase in phagocytosis over isotype control of 32.28% in the combination vs 11.78% with rituximab alone, n = 24, p < 0.0001). Upon coculture of Jurkat cells with macrophages, SRF231 not only induced phagocytosis (EC50, 332 ± 65 ng/mL, n = 3), but also induced cell death of non-phagocytosed target tumor cells (EC50, 295 ± 43 ng/mL, n = 3). While soluble SRF231 did not induce significant target tumor cell killing, immobilized SRF231 induced Jurkat cell and primary CLL cell death (median % alive of 34.6% in SRF231 treated cells vs 64.4% in controls, n = 24, p < 0.0001). To assess the mechanism of cell death induction, tumor cells were pretreated with a pan-caspase inhibitor, Z-VAD-FMK, which revealed that SRF231-mediated tumor cell death is caspase-independent. In primary CLL cells, BH3 profiling confirmed that SRF231 did not alter mitochondrial priming for apoptosis or pro-survival Bcl-2 family protein dependencies. Pre-treatment with the phospholipase C (PLC) inhibitor U73122 prior to SRF231 exposure partially blocked the ability of SRF231 to kill CLL cells (median % alive of 45.4% in pre-treated cells vs 25.4% in controls, n = 6, p = 0.0029). In addition to these in vitro studies, SRF231 displayed profound antitumor activity in a xenograft model of B-cell lymphoma as a single agent, and led to complete and durable tumor regression in combination with VEN. Conclusion Ex vivo treatment of primary CLL cells with SRF231 led to dual antitumor effects of tumor cell-extrinsic plus -intrinsic mechanisms by augmenting rituximab-induced phagocytosis and inducing tumor cell death. SRF231 induced death of tumor cells through a caspase-independent mechanism that depends at least partially on PLC. In vivo, SRF231 in combination with VEN led to complete and durable tumor regression in a xenograft model. SRF231 is currently being evaluated across multiple tumor types in a Phase 1 clinical trial (NCT03512340). Disclosures Valentin: Roche: Other: Travel reimbursement; AbbVie: Other: Travel reimbursement. Peluso:Surface Oncology: Employment, Equity Ownership. Adam:Surface Oncology: Employment, Equity Ownership. Zhang:Surface Oncology: Employment, Equity Ownership. Armet:Surface Oncology: Employment, Equity Ownership. Guerriero:GSK: Research Funding; Eli Lilly: Research Funding. Lee:Surface Oncology: Employment, Equity Ownership. Palombella:Surface Oncology: Employment, Equity Ownership. Holland:Surface Oncology: Employment, Equity Ownership. Paterson:Surface Oncology: Employment, Equity Ownership. Davids:Surface Oncology: Research Funding; Celgene: Consultancy; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; MEI Pharma: Consultancy, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Effects Of Inhibition Of XPO1/CRM1-Dependent Nuclear Export By Selinexor (KPT-330), Alone and In Combination With Carfilzomib (CFZ), On Apoptosis and Autophagy In Multiple Myeloma (MM)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 279-279 ◽  
Author(s):  
Shaun Rosebeck ◽  
Malathi Kandarpa ◽  
Mattina M. Alonge ◽  
Jagoda Jasielec ◽  
Dominik Dytfeld ◽  
...  
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Board Of Directors ◽  
Nuclear Export ◽  
Research Funding ◽  
Proteasome Inhibition ◽  
Employment Equity ◽  
Advisory Committees ◽  
Nuclear Retention ◽  
Equity Ownership

Abstract Introduction Exportin 1 (XPO1/CRM1) is the sole transporter of most tumor suppressor proteins (TSP) from the nucleus to the cytoplasm. Small molecule selective inhibitors of nuclear export (SINE) block XPO1-mediated nuclear export, leading to nuclear retention of TSP, inducing cancer cell death and sensitizing cancer cells to other cytotoxic drugs. Although the cytotoxic and apoptotic effects of SINE on different cancer cells have now been established, the mechanism of cell death is still not fully understood. Recently, autophagy emerged as a possible cell death pathway and alternate to the ubiquitin-proteasome pathway (UPP) by which excess and/or dysfunctional proteins and organelles are degraded and recycled. MM cells require basal autophagy for survival and caspase 10 protease activity is required to limit autophagic cell death. The possibility that autophagy may be involved in the mechanism of action of SINE is supported by observations that knockdown of XPO1 can promote autophagy and that cytoplasmic p53 can repress autophagy. In this study, we evaluated the contribution of autophagy to the effects of Selinexor (KPT-330), a SINE currently in two phase I clinical trials, on MM cell cytotoxicity. Because proteasome inhibition can also induce autophagy, we hypothesized that the combination of Selinexor and CFZ, a next generation irreversible proteasome inhibitor approved for treatment of MM, may synergistically augment cytotoxicity in MM cells. Methods Plasma cells (PC) were purified from consented MM patient bone marrow aspirates using EasySep (Stem Cell Technology). PC purity (>80%) was determined by Wright-Giemsa staining of cytospins. Human myeloma cell lines (HMCL) NCI-H929, RPMI-8226, MM1.S and MM1.R were cultured in RPMI1640 with 10% FBS. IC50 values were determined using GraphPad Prism. Drug combination efficacy was determined using CalcuSyn (Biosoft). Combination index (CI) values <1.0 indicate synergy. Transcription factor profiling plate array II was from Signosis (Sunnyvale, CA). Otherwise, our studies used standard cellular and molecular biology techniques. Results Selinexor caused significant cytotoxicity in HMCL (IC50 10-100 nM), induced cell cycle arrest in G1, and promoted apoptotic cell death typified by caspase activation, DNA fragmentation, and Annexin V binding. Importantly, purified PC from newly-diagnosed MM patients were also sensitive to the cytotoxic effects of Selinexor. HMCL treated with KPT-330 also exhibited nuclear retention of p53. To gain insight into more global effects of SINE treatment, we assayed DNA binding activity of approx. 100 different transcription factors. TSP, such as Rb, p53, and EGR-1, exhibited increased activity, whereas proto-oncogenes, including NF-κB, Myc, and Myb, were inactivated in response to KPT-330. Western blot analysis of inactivated targets showed nearly total loss of protein. Unlike XPO1, which is degraded via the UPP upon treatment with SINE, loss of Myc and NF-κB subunits, including RelA, RelB, and p52, could not be reversed by proteasome inhibition. Instead, we found that Selinexor treatment induced markers of autophagy, including LC3B induction and processing, and promoted loss of caspase 10, which is associated with autophagic cell death in MM. Importantly, we have determined that the combination of Selinexor and CFZ results in synergistic cell death (CI 0.2-0.6) characterized by enhanced induction of both apoptosis and autophagy in HMCL. The effects of Selinexor and CFZ were also evaluated in NOD-SCID mice inoculated subcutaneously with NCI-H929 cells. Mice were treated 3 times weekly per oswith Selinexor (5 or 10 mg/kg) alone and in combination with twice-weekly IV-administered CFZ (1.5 or 3 mg/kg). After 16 days of treatment, high doses of either CFZ or Selinexor alone moderately inhibit tumor growth. Treatment with the combination of CFZ and Selinexor at all dose levels was more effective than single agent treatment, and high dose combination treatment completely impaired xenograft tumor growth with good tolerability. Conclusion Our studies are the first to suggest that Selinexor-induced cell death correlates with both apoptosis and autophagy, and that both cell death pathways are enhanced in response to combined treatment with CFZ. Overall, our pre-clinical study provides strong rationale for evaluation of Selinexor in combination with CFZ for the treatment of MM. Disclosures: McCauley: Karyopharm Therapeutics Inc.: Employment, Equity Ownership, Patents & Royalties. Shacham:Karyopharm Therapeutics Inc.: Employment, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Patents & Royalties. Kauffman:Karyopharm Therapeutics Inc.: Employment, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Patents & Royalties. Jakubowiak:BMS: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Millennium: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Onyx: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau.

scholarly journals Successful Plerixafor-Mediated Mobilization, Apheresis, and Lentiviral Vector Transduction of Hematopoietic Stem Cells in Patients with Severe Sickle Cell Disease

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 990-990
Author(s):  
John F Tisdale ◽  
Francis J. Pierciey ◽  
Rammurti Kamble ◽  
Julie Kanter ◽  
Lakshmanan Krishnamurti ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Board Of Directors ◽  
Sickle Cell ◽  
Research Funding ◽  
Ex Vivo ◽  
Cell Disease ◽  
Employment Equity ◽  
Advisory Committees ◽  
Cd34 Cells ◽  
Equity Ownership

Abstract Background Patients with severe sickle cell disease (SCD) may benefit from β-globin gene transfer into autologous hematopoietic stem cells (HSC). Successful HBB gene transfer requires vector-mediated transduction of primitive HSCs. Steady-state bone marrow (BM) is the default HSC source in patients with SCD. Normal human BM contains up to 30% CD34+CD19+ pro-B cells and other lineage-committed cell types (CD34dim) that will not contribute to improved long-term erythropoiesis via gene therapy; these cells mobilize at low rates. CD34+ cell yields from BM harvest (BMH) are typically lower than those after mobilization and peripheral blood (PB) apheresis; multiple rounds of BMH may be required to obtain adequate cell doses for autologous gene therapy (GT) protocols. As G-CSF can cause life-threatening SCD complications and is contraindicated, plerixafor, a CXCR4 receptor antagonist, may accomplish HSC mobilization without the neutrophil or endothelial activation that elicit vaso-occlusion. We modified the protocol for the HGB-206 phase 1 study of LentiGlobin GT in severe SCD (NCT02140554) to assess HSC mobilization with plerixafor alone, followed by apheresis and transduction of mobilized cells. We also characterized BM-derived and plerixafor-mobilized HSC populations from patients with SCD. Methods HGB-206 is a phase 1 study of LentiGlobin Drug Product (DP), which contains autologous HSCs transduced ex vivo with the betibeglogene darolentivec (BB305) lentiviral vector, in patients with severe SCD (defined as a history of recurrent vaso-occlusive crisis [VOC], acute chest syndrome, stroke, or tricuspid regurgitant jet velocity of &gt;2.5 m/s). Patients in group B receive 240 µg/kg plerixafor followed 4-6 hours later by apheresis, processing ~3 total blood volumes to collect backup HSCs. If &lt; 1.5 x 106 CD34+ cells are collected, patients undergo a second day of apheresis. Cells collected in excess of those required for backup in case of graft failure are transduced with BB305 lentiviral vector for exploratory analyses. Group B patients then proceed to BMH to obtain cells for clinical DP manufacture. Group C will receive DP manufactured from mobilized PB. Mass cytometry (CyTOF) was used to analyze ex vivo cultured CD34+ cells with over 35 cell surface markers. Results To date, 3 patients have undergone plerixafor mobilization. Patients had a transient 1.5- to 3-fold increase in peak white blood cell and absolute neutrophil levels after plerixafor. Peak absolute CD34+ cell counts in PB were 170, 58, and 160 x 106 CD34+ cells/liter. A total of 15.3, 5.6, and 9.0 x 106 CD34+ cells/kg were collected in a single day of apheresis, and no subsequent apheresis or mobilization was required. In the same study, a mean of 5.0 (range 0.3-10.8) x 106 CD34+ cells/kg were collected per BMH (N=21). The mobilization and apheresis procedures had an acceptable toxicity profile. No dose-limiting toxicities were observed after plerixafor dosing. One patient had a single VOC approximately 48 hours after receiving plerixafor; this patient also experienced VOCs of similar severity after BMH. In contrast, after 21 BMHs in 9 patients, 18 ≥ grade 3 AEs were reported in 6 patients, primarily pain. Ex vivo cultured CD34+ cells isolated from BMH consisted of an average of 41.0% (17.3%-50.7%) CD34dim cells, with 16%-50% of the CD34dim cells expressing lymphoid markers. In contrast, ex vivo cultured CD34+ cells isolated from plerixafor mobilized PB contained an average of 8.2% (1.5-19.5%) CD34dim cells. Similar drug product vector copy numbers were obtained after research-scale transduction of CD34+ cells from marrow and PB from the same patient. Conclusion Initial results suggest that obtaining adequate doses of CD34+ cells from plerixafor-mobilized PB of patients with SCD may be safe and feasible, without the life-threatening complications associated with G-CSF, and with fewer, less invasive procedures compared with BMH. PB-derived CD34+ cells may contain lower proportions of lineage-committed CD34+ cells than BM-derived cells from patients with SCD. Cells collected by BMH and PB mobilization/apheresis appear to have an equivalent transduction efficiency. Together these results indicate that it may be possible to use plerixafor-only mobilization in clinical studies of autologous HSC GT in SCD. Results of mobilization, apheresis, and DP manufacturing at clinical scale for additional patients will be available for presentation. Disclosures Pierciey: bluebird bio: Employment. Kanter: American Society of Hematology (Sickle Cell Disease Guideline Panel): Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; MUSC: Other: The site PI for sponsored research conducted at MUSC who receives funds from: Novartis, bluebird bio, GBT, Sancillo, Apopharma, Pfizer; NHLBI (sickle cell disease research advisory committee): Membership on an entity's Board of Directors or advisory committees, Research Funding; Sancillo: Research Funding; Apopharma: Research Funding; Pfizer: Research Funding; GBT: Research Funding; Bluebird Bio: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kwiatkowski: Novartis: Research Funding; Bluebird Bio: Research Funding; Apopharma: Research Funding; Agios: Consultancy, Honoraria; Ionis: Consultancy, Honoraria. Thompson: Novartis: Consultancy, Research Funding; bluebird bio: Consultancy, Research Funding; Baxalta: Research Funding; Celgene: Consultancy, Research Funding. Shestopalov: bluebird bio: Employment, Equity Ownership. Bonner: bluebird bio: Employment, Equity Ownership. Joseney-Antoine: bluebird bio: Employment, Equity Ownership. Asmal: bluebird bio: Employment, Equity Ownership. Walters: bluebird bio: Research Funding; ViaCord Processing Lab: Other: Medical Director; Sangamo Therapeutics: Consultancy; AllCells, Inc: Other: Medical Director.

Transient Inhibition of Transforming Growth Factor-β1 in Human Blood-Derived CD34+ Cells Enhances Survival and Proliferation in Vitro and Vascular Reparative functions In Vivo.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3546-3546
Author(s):  
Stephen Bartelmez ◽  
Ashay Bhatwadekar ◽  
Patrick Iversen ◽  
Francis W Ruscetti ◽  
Maria Grant
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Ex Vivo ◽  
Cxcr4 Expression ◽  
Employment Equity ◽  
Advisory Committees ◽  
Cd34 Cells ◽  
Equity Ownership ◽  
Tgf Β1

Abstract Abstract 3546 Poster Board III-483 CD34+ cells from diabetic patients demonstrate reduced vascular reparative function due to decreased proliferation as well as diminished migration prowess which is largely due to lower levels of bioavailable nitric oxide (NO). We asked whether a transient TGF-β1 blockade in CD34+ cells from diabetics would improve their reparative ability given that TGF-β is a key factor modulating stem cell quiescence. Peripheral blood lin-CD34+ cells or lin-CD34+CD38+/− cells were treated ex vivo with antisense phosphorodiamidate morpholino oligomers (TGF-β1 -PMO), demonstrated to inhibit TGF-β1 protein expression in stem cells. Cells were then analyzed for cell surface TGF-β Receptor 2 (TGF-β R2) and CXCR4 expression, their ability to generate NO, their ability to migrate toward SDF-1, their ability to survive in the absence of added growth factors, and tested in vivo for their vascular reparative ability. After TGF-β1-PMO treatment, healthy and diabetic CD34+CD38+ and - cells downregulated TGF-βR2, upregulated CXCR4 expression, survived in the absence of added growth factors ex vivo and migrated more efficiently to SDF-1 compared to controls. TGF-β1-PMO treated diabetic CD34+ cells restored NO production to non-diabetic levels. In contrast, TGF-β1-PMO did not enhance NO generation in CD34+ cells from healthy subjects. Using an in vivo retinal ischemia reperfusion model, we observed that TGF-β1-PMO treatment increased the ability of both healthy and diabetic CD34+ cells to home to injured capillaries compared to control PMO treated cells. As also observed in our current study, a reduction of TGF-β1 levels in murine hematopoietic stem cells correlates with a reduction in TGF-βR2 expression which may induce proliferation in vivo. We also show that both diabetic and healthy lin-CD34+CD38+ cells express TGF-βR2 by FACS. In contrast, only healthy lin-CD34+CD38- cells expressTGF-βR2 while diabetic lin-CD34+CD38 - cells express essentially no cell surface TGF-βR2 (<5 % of cells are TGF-βR2+). Our results suggest that a transient blockade of TGF-β1 may represent a promising therapeutic strategy in restoring vascular reparative function in diabetic CD34+ cells. Disclosures: Bartelmez: BetaStem Therapeutics: Employment, Equity Ownership, Head, SRB, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. Iversen:AVI-Biopharma: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding.

Broad Activity of Apto-253 in AML and Other Hematologic Malignancies Correlates with KLF4 Expression Level

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1358-1358 ◽  
Author(s):  
Stephen E. Kurtz ◽  
Daniel Bottomly ◽  
Beth Wilmot ◽  
Shannon K. McWeeney ◽  
William Rice ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Board Of Directors ◽  
Research Funding ◽  
Drug Sensitivity ◽  
Ex Vivo ◽  
Hematologic Malignancies ◽  
Employment Equity ◽  
Advisory Committees ◽  
Flt3 Inhibitor ◽  
Equity Ownership

Abstract Introduction: Aberrant expression of the homeodomain transcription factor CDX2 has recently been reported in a large proportion of AML cases. One consequence of CDX2 deregulation appears to be repressed expression of the transcription factor KLF4. Repression of KLF4 was shown to be critical for CDX2-mediated tumorigenesis, and forced genetic de-repression of KLF4 led to apoptosis of AML cells. APTO-253 is a novel small molecule that induces the expression of KLF4 and is cytotoxic to AML cell lines at low-nanomolar concentrations. We evaluated the activity of APTO-253 against a broad panel of primary specimens from patients with acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), and myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN). APTO-253 was tested both as a single agent and in combinations with 2 other emerging targeted therapies, the BET bromodomain inhibitor JQ1 and the FLT3 inhibitor quizartinib. Methods: We used an ex vivo drug sensitivity assay to determine the activity of APTO-253, JQ1, and quizartinib across increasing concentrations of each agent up to 10 μM. Combinations were tested at fixed, equimolar ratios over the same concentration range. After a 3-day ex vivo culture, cell viability was assessed using a colorimetric tetrazolium-based MTS assay, and IC50 values were calculated. RNA-Seq was performed on AML specimens to permit investigation of correlations of drug sensitivity with gene expression levels. Results: We evaluated specimens from 177 patients with a variety of hematologic malignancy diagnoses (80 AML, 72 CLL, 25 MDS/MPN). The highest frequency of APTO-253 sensitivity occurred in AML, with 43/80 (54%) samples exhibiting an IC50 <1 μM. At this cutoff, 25/72 (35%) CLL samples and 3/25 (12%) MDS/MPN samples were sensitive to APTO-253. The average expression of KLF4 mRNA was 2-fold lower among AML samples with an IC50 <1 µM compared to those with IC50 >1 µM (p=0.07). Approximately 65% (56/87) of cases tested with a combination of APTO-253 and JQ1 showed the combination IC50 to be at least 2-fold lower than the IC50 of either agent alone. This enhanced efficacy of APTO-253 with JQ1 was observed across all 3 hematologic malignancies tested, whereas quizartinib enhancement of APTO-253 sensitivity was confined to AML (14/38, or 37% showed reduced IC50). Conclusions: These results support the potential of KLF4 as an important and frequently dysregulated master transcription factor in AML and suggest that the KLF4 inducer APTO-253 is effective at killing tumor cells in a majority of AML samples. The data also indicate activity of APTO-253 in other hematologic malignancies, namely CLL. Expression level of KLF4 may be one component of a biomarker for prediction of APTO-253 efficacy; a more extensive global gene expression signature analysis is under way. Finally, these data have identified prominent interaction of APTO-253 with the BET bromodomain inhibitor JQ1, as well as AML-restricted interaction of APTO-253 with the FLT3 inhibitor quizartinib, suggesting these classes of drugs as potential combination partners for APTO-253. Disclosures Rice: Aptose Biosciences: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Howell:Aptose Biosciences: Consultancy, Equity Ownership; Angstrom: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Abeoda: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; InhibRx: Equity Ownership. Vellanki:Aptose Biosciences: Employment, Equity Ownership. Druker:Oncotide Pharmaceuticals: Research Funding; Sage Bionetworks: Research Funding; Fred Hutchinson Cancer Research Center: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis Pharmaceuticals: Research Funding; Henry Stewart Talks: Patents & Royalties; McGraw Hill: Patents & Royalties; Leukemia & Lymphoma Society: Membership on an entity's Board of Directors or advisory committees, Research Funding; Blueprint Medicines: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Oregon Health & Science University: Patents & Royalties; MolecularMD: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees; ARIAD: Research Funding; AstraZeneca: Consultancy; Aptose Therapeutics, Inc (formerly Lorus): Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; CTI Biosciences: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Millipore: Patents & Royalties; Roche TCRC, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cylene Pharmaceuticals: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Tyner:Incyte: Research Funding; Janssen Pharmaceuticals: Research Funding; Constellation Pharmaceuticals: Research Funding; Array Biopharma: Research Funding; Aptose Biosciences: Research Funding.

CC-122 Expands Activated and Memory CD4 and CD8 T Cells In Vivo and Induces T Cell Activation Ex Vivo in Subjects with Relapsed or Refractory Diffuse Large B Cell Lymphoma and Multiple Myeloma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2704-2704 ◽  
Author(s):  
Anita K. Gandhi ◽  
Ribrag Vincent ◽  
Cecilia Carpio ◽  
Anne-Marie Stoppa ◽  
Mecide Meric Gharibo ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Ex Vivo ◽  
T Helper ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Median Change

Abstract Background: CC-122 is a first in class PPMTM pleiotropic pathway modifier compound with multiple biological activities including potent anti-proliferative activity against B lineage cells, anti-angiogenic activity and immunomodulatory effects. CC-122 binds cereblon, and promotes ubiquitination of lymphoid transcription factors Ikaros and Aiolos, leading to their subsequent degradation resulting in activation of T cells. The immunological properties of CC-122 including effects on T cell subset number in vivo and T cell cytokine production ex vivo was explored in subjects with advanced aggressive non-Hodgkin Lymphoma (NHL) and Multiple Myeloma (MM) enrolled in a Phase 1b trial (NCT01421524) at 3 mg QD and 4 and 5 mg 5/7 days dosed in 28 day cycles until disease progression. Methods: As of June 25, 2015, 76 total DLBCL and MM subjects were enrolled in the expansion phase of the study. Assessments for T cell subset numbers were performed at screening (baseline), cycle 1 day 15 (C1D15), cycle 1 day 22, cycle 2 day 15 and cycle 2 day 22 by flow cytometric immunophenotyping of fresh whole blood. Ex vivo whole blood T cell activation as measured by IL-2, IL-6, IFNg and GM-CSF cytokine production was performed using the anti-CD3 TruCulture Assay. Changes from baseline were evaluated using the t test with p<0.05 considered significant. Results: T cell subsets which were significantly changed are shown in italics in Table 1. In MM subjects (n=19-21) and DLBCL subjects (n=30-31), CC-122 treatment significantly expanded several T cell activator and memory T cell subsets while decreasing naïve T cells. A single dose of CC-122 on C1D1 activated T cells as measured in an ex vivo T cell activation assay in MM subjects (n=6-13) and DLBCL subjects (n=5-12) (Table 2). In addition, we evaluated potential correlations of clinical outcome with baseline biomarker and biomarker changes upon CC-122 treatment. Table 1. MM n=19-21 NHL n=30-31 T cell Parameter Phenotype Baseline cells/mm3 Median % Change at C1D15 from Baseline P Baseline cells/mm3 Median % Change at C1D15 from Baseline P Total T cells ABS CD3+ 636.9 17.733 0.24747 522.94 43.83 0.03638 Total T helper ABS CD3+/CD4+/CD8- 275.38 18.333 0.07812 238.96 13.428 0.09893 T helper Activated ABS CD3+/CD4+/CD8-/HLA-DR+ 62.34 105.769 0.00238 57.11 78.571 0.01567 T helper Total Naïve ABS CD3+/CD4+/CD8-/45RA+/45RO- 69.07 -54.545 0.0038 47.94 -47.841 0.03159 T helper Effector CD62L+ ABS CD3+/CD4+/CD8-/45RA+/62L+ 117.62 0 0.16621 93.74 -6 0.14611 T helper Effector CD62L- ABS CD3+/CD4+/CD8-/45RA+/62L- 21.38 -25.862 0.15196 28.44 -20.161 0.08548 T helper Total Memory ABS CD3+/CD4+/CD8-/45RA-/45RO+ 137.93 41.176 0.05373 119.15 36 0.01915 T helper Central Memory ABS CD3+/CD4+/CD8-/45RA-/62L+ 91.9 47.451 0.01953 75.74 37.143 0.01275 T helper Effector Memory ABS CD3+/CD4+/CD8-/45RA-/62L- 44.17 18.147 0.17768 41.07 19.375 0.04749 Total T cytotoxic ABS CD3+/CD4-/CD8+ 334.07 18.044 0.27499 265.7 43.823 0.0127 T cytotoxic Activated ABS CD3+/CD4-/CD8+ /HLA-DR+ 176.76 100 0.20781 121.3 96.454 0.00686 T cytotoxic Total Naïve ABS CD3+/CD4-/CD8+ /45RA+/45RO- 173.69 -35.714 0.15126 116.04 -32.667 0.89774 T cytotoxic Effector CD62L+ ABS CD3+/CD4-/CD8+ /45RA+/62L+ 127.28 20.727 0.24151 93.43 17.419 0.09599 T cytotoxic Effector CD62L- ABS CD3+/CD4-/CD8+ /45RA+/62L- 151.72 -14.286 0.28394 120.98 -18.301 0.18068 T cytotoxic Total Memory ABS CD3+/CD4-/CD8+ /45RA-/45RO+ 55.03 167.402 0.26292 54.13 184.615 0.01034 T cytotoxic Central Memory ABS CD3+/CD4-/CD8+ /45RA-/62L+ 26.83 160.417 0.00013 18.78 264.087 0.00169 T cytotoxic Effector Memory ABS CD3+/CD4-/CD8+ /45RA-/62L- 28.14 133.333 0.00107 32.59 100 0.01939 Table 2. MM n=6-13 NHL n=5-12 Cytokine Baseline cells/mm3 Median % Change from Baseline P Baseline cells/mm3 Median % Change from Baseline P IL-2 98.71 603.509 0.01329 104.5 437.194 0.01761 IL-6 131.84 124.108 0.03426 99.64 21.68 0.2692 GM-CSF 90.24 636.207 0.06608 212.96 144.601 0.16744 IFNg 271.85 404.98 0.0056 554.64 162.451 0.03024 Conclusions: CC-122 significantly increases the proportion of several cytotoxic and helper T cells subsets while decreasing naïve T cells in both DLBCL and MM subjects. CC-122 also significantly activates T cells ex vivo as measured by cytokine production. These results indicate that CC-122 is a potent modulator of T cell numbers and activation and this may serve as rationale for combinations with other immunotherapies. Disclosures Gandhi: Celgene: Employment, Equity Ownership. Off Label Use: CC-122 is a first in class PPM(TM) pleiotropic pathway modifier with multiple biological activities against B lineage cells. Vincent:Pharmamar: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Esai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding. Carpio:Celgene: Research Funding. Stoppa:Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Gharibo:Celgene: Research Funding. Damian:Celgene: Research Funding. Rasco:Celgene: Research Funding; Asana BioSciences, LLC: Research Funding. Ysebaert:Celgene: Research Funding. Cordoba:Celgene: Research Funding. Edenfield:Celgene: Research Funding. Pinto:Celgene Corporation: Honoraria; Takeda: Honoraria, Research Funding; Spectrum: Honoraria. López-Martín:Celgene: Research Funding. Sancho:Celgene: Research Funding. Panizo:Janssen: Speakers Bureau; Takeda: Speakers Bureau; Roche: Speakers Bureau; Celgene: Research Funding. Wei:Celgene: Employment, Equity Ownership. Hagner:Celgene: Employment, Equity Ownership. Waldman:Celgene: Employment, Equity Ownership. Hege:Celgene Corporation: Employment, Equity Ownership. Chopra:Celgene Corporation: Employment, Equity Ownership. Pourdehnad:Celgene: Employment.

scholarly journals Rapid and Robust Mobilization of CD34+ HSCs without G-CSF Following Administration of Mgta-145 Alone or in Combination with Plerixafor

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1961-1961
Author(s):  
John F. DiPersio ◽  
Jonathan Hoggatt ◽  
Steven Devine ◽  
Lukasz Biernat ◽  
Haley Howell ◽  
...  
Keyword(s):  
Single Dose ◽  
Adverse Events ◽  
Board Of Directors ◽  
Preliminary Data ◽  
Research Funding ◽  
Fold Change ◽  
Employment Equity ◽  
Advisory Committees ◽  
Cd34 Cells ◽  
Equity Ownership

Background Granulocyte colony-stimulating factor (G-CSF) is the standard of care for mobilization of hematopoietic stem cells (HSCs). G-CSF requires 4-7 days of injections and often multiple aphereses to acquire sufficient CD34+ cells for transplant. The number of CD34+ HSCs mobilized can be variable and patients who fail to mobilize enough CD34+ cells are treated with the combination of G-CSF plus plerixafor. G-CSF use is associated with bone pain, nausea, headaches, fatigue, rare episodes of splenic rupture, and is contraindicated for patients with autoimmune and sickle cell disease. MGTA-145 (GroβT) is a CXCR2 agonist. MGTA-145, in combination with plerixafor, a CXCR4 inhibitor, has the potential to rapidly and reliably mobilize robust numbers of HSCs with a single dose and same-day apheresis for transplant that is free from G-CSF. MGTA-145 plus plerixafor work synergistically to rapidly mobilize HSCs in both mice and non-human primates (Hoggatt, Cell 2018; Goncalves, Blood 2018). Based on these data, Magenta initiated a Phase 1 dose-escalating study to evaluate the safety, PK and PD of MGTA-145 as a single agent and in combination with plerixafor. Methods This study consists of four parts. In Part A, healthy volunteers were dosed with MGTA-145 (0.0075 - 0.3 mg/kg) or placebo. In Part B, MGTA-145 dose levels from Part A were selected for use in combination with a clinically approved dose of plerixafor. In Part C, a single dose MGTA-145 plus plerixafor will be administered on day 1 and day 2. In Part D, MGTA-145 plus plerixafor will be administered followed by apheresis. Results MGTA-145 monotherapy was well tolerated in all subjects dosed (Table 1) with no significant adverse events. Some subjects experienced mild (Grade 1) transient lower back pain that dissipated within minutes. In the ongoing study, the combination of MGTA-145 with plerixafor was well tolerated, with some donors experiencing Grade 1 and 2 gastrointestinal adverse events commonly observed with plerixafor alone. Pharmacokinetic (PK) exposure and maximum plasma concentrations increased dose proportionally and were not affected by plerixafor (Fig 1A). Monotherapy of MGTA-145 resulted in an immediate increase in neutrophils (Fig 1B) and release of plasma MMP-9 (Fig 1C). Neutrophil mobilization plateaued within 1-hour post MGTA-145 at doses greater than 0.03 mg/kg. This plateau was followed by a rebound of neutrophil mobilization which correlated with re-expression of CXCR2 and presence of MGTA-145 at pharmacologically active levels. Markers of neutrophil activation were relatively unchanged (<2-fold vs baseline). A rapid and statistically significant increase in CD34+ cells occurred @ 0.03 and 0.075 mg/kg of MGTA-145 (p < 0.01) relative to placebo with peak mobilization (Fig 1D) 30 minutes post MGTA-145 (7-fold above baseline @ 0.03 mg/kg). To date, the combination of MGTA-145 plus plerixafor mobilized >20/µl CD34s in 92% (11/12) subjects compared to 50% (2/4) subjects receiving plerixafor alone. Preliminary data show that there was a significant increase in fold change relative to baseline in CD34+ cells (27x vs 13x) and phenotypic CD34+CD90+CD45RA- HSCs (38x vs 22x) mobilized by MGTA-145 with plerixafor. Mobilized CD34+ cells were detectable at 15 minutes with peak mobilization shifted 2 - 4 hours earlier for the combination vs plerixafor alone (4 - 6h vs 8 - 12h). Detailed results of single dose administration of MGTA-145 and plerixafor given on one day as well as also on two sequential days will be presented along with fully characterized graft analysis post apheresis from subjects given MGTA-145 and plerixafor. Conclusions MGTA-145 is safe and well tolerated, as a monotherapy and in combination with plerixafor and induced rapid and robust mobilization of significant numbers of HSCs with a single dose in all subjects to date. Kinetics of CD34+ cell mobilization for the combination was immediate (4x increase vs no change for plerixafor alone @ 15 min) suggesting the mechanism of action of MGTA-145 plus plerixafor is different from plerixafor alone. Preliminary data demonstrate that MGTA-145 when combined with plerixafor results in a significant increase in CD34+ fold change relative to plerixafor alone. Magenta Therapeutics intends to develop MGTA-145 as a first line mobilization product for blood cancers, autoimmune and genetic diseases and plans a Phase 2 study in multiple myeloma and non-Hodgkin lymphoma in 2020. Disclosures DiPersio: Magenta Therapeutics: Equity Ownership; NeoImmune Tech: Research Funding; Cellworks Group, Inc.: Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Consultancy; Incyte: Consultancy, Research Funding; RiverVest Venture Partners Arch Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; WUGEN: Equity Ownership, Patents & Royalties, Research Funding; Macrogenics: Research Funding, Speakers Bureau; Bioline Rx: Research Funding, Speakers Bureau; Celgene: Consultancy; Amphivena Therapeutics: Consultancy, Research Funding. Hoggatt:Magenta Therapeutics: Consultancy, Equity Ownership, Research Funding. Devine:Kiadis Pharma: Other: Protocol development (via institution); Bristol Myers: Other: Grant for monitoring support & travel support; Magenta Therapeutics: Other: Travel support for advisory board; My employer (National Marrow Donor Program) has equity interest in Magenta. Biernat:Medpace, Inc.: Employment. Howell:Magenta Therapeutics: Employment, Equity Ownership. Schmelmer:Magenta Therapeutics: Employment, Equity Ownership. Neale:Magenta Therapeutics: Employment, Equity Ownership. Boitano:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Cooke:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Goncalves:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Raffel:Magenta Therapeutics: Employment, Equity Ownership. Falahee:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Morrow:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Davis:Magenta Therapeutics: Employment, Equity Ownership.

scholarly journals Treatment Patterns and Outcomes in Elderly Patients with Newly Diagnosed Multiple Myeloma: Results from the Connect® MM Registry

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3129-3129
Author(s):  
Hans C. Lee ◽  
Sikander Ailawadhi ◽  
Cristina Gasparetto ◽  
Sundar Jagannath ◽  
Robert M. Rifkin ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Causes Of Death ◽  
Age Groups ◽  
Treatment Patterns ◽  
Age Group ◽  
Newly Diagnosed ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Background: Multiple myeloma (MM) is common among the elderly, with 35% of patients (pts) diagnosed being aged ≥75 years (y). With increasing overall life expectancy, the incidence and prevalence of newly diagnosed and previously treated MM patients ≥80 y is expected to increase over time. Because elderly pts are often excluded from clinical trials, data focused on their treatment patterns and clinical outcomes are lacking. The Connect® MM Registry (NCT01081028) is a large, US, multicenter, prospective observational cohort study of pts with newly diagnosed MM (NDMM) designed to examine real-world diagnostic patterns, treatment patterns, clinical outcomes, and health-related quality of life patient-reported outcomes. This analysis reviews treatment patterns and outcomes in elderly pts from the Connect MM Registry. Methods: Pts enrolled in the Connect MM registry at 250 community, academic, and government sites were included in this analysis. Eligible pts were adults aged ≥18 y with symptomatic MM diagnosed ≤2 months before enrollment, as defined by International Myeloma Working Group criteria; no exclusion criteria were applied. For this analysis, pts were categorized into 4 age groups: <65, 65 to 74, 75 to 84, and ≥85 y. Pts were followed from time of enrollment to the earliest of disease progression (or death), loss to follow-up, or data cutoff date of February 7, 2019. Descriptive statistics were used for baseline characteristics and treatment regimens. Survival outcomes were analyzed using Cox regression. Time to progression (TTP) analysis excluded causes of death not related to MM. Results: Of 3011 pts enrolled (median age 67 y), 132 (4%) were aged ≥85 y, and 615 (20%) were aged 75-84 y at baseline. More pts aged ≥85 y had poor prognostic factors such as ISS stage III disease and reduced hemoglobin (<10 g/dL or >2 g/dL <LLN) compared with other age groups, although no notable differences between creatinine and calcium levels were observed across age groups (Table). A lower proportion of elderly pts (75-84 and ≥85 y) received triplet regimens as frontline therapy. More elderly pts received a single novel agent, whereas use of 2 novel agents was more common in younger pts (Table). The most common frontline regimens among elderly pts were bortezomib (V) + dexamethasone (D), followed by lenalidomide (R) + D, whereas those among younger pts included RVD, followed by VD and CyBorD (Table). No pt aged ≥85 y, and 4% of pts aged 75-84 y received high-dose chemotherapy and autologous stem cell transplant (vs 61% in the <65 y and 37% in the 65-74 y age group). The most common maintenance therapy was RD in pts ≥85 y (although the use was low) and R alone in other age groups (Table). In the ≥85 y group, 27%, 10%, and 4% of pts entered 2L, 3L, and 4L treatments respectively, vs 43%, 23%, and 13% in the <65 y group. Progression-free survival was significantly shorter in the ≥85 y age group vs the 75-84 y age group (P=0.003), 65-74 y age group (P<0.001), and <65 y age group (P<0.001; Fig.1). TTP was significantly shorter in the ≥85 y group vs the <65 y group (P=0.020); however, TTP was similar among the 65-74 y, 75-84 y, and ≥85 y cohorts (Fig. 2). Overall survival was significantly shorter in the ≥85 y group vs the 75-84 y, 65-74 y, and <65 y groups (all P<0.001; Fig. 3). The mortality rate was lowest (46%) during first-line treatment (1L) in pts aged ≥85 y (mainly attributed to MM progression) and increased in 2L and 3L (47% and 54%, respectively); a similar trend was observed in the younger age groups. The main cause of death was MM progression (29% in the ≥85 y vs 16% in the <65 y group). Other notable causes of death in the ≥85 y group included cardiac failure (5% vs 2% in <65 y group) and pneumonia (5% vs 1% in <65 y group). Conclusions: In this analysis, elderly pts received similar types of frontline and maintenance regimens as younger pts, although proportions varied with decreased use of triplet regimens with age. Considering similarities in TTP across the 65-74 y, 75-84 y, and ≥85 y cohorts, these real-world data support active treatment and aggressive supportive care of elderly symptomatic pts, including with novel agents. Additionally, further clinical studies specific to elderly patients with MM should be explored. Disclosures Lee: Amgen: Consultancy, Research Funding; GlaxoSmithKline plc: Research Funding; Sanofi: Consultancy; Daiichi Sankyo: Research Funding; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Ailawadhi:Janssen: Consultancy, Research Funding; Takeda: Consultancy; Pharmacyclics: Research Funding; Amgen: Consultancy, Research Funding; Celgene: Consultancy; Cellectar: 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 . Jagannath:AbbVie: Consultancy; Merck & Co.: Consultancy; Bristol-Myers Squibb: Consultancy; Karyopharm Therapeutics: Consultancy; Celgene Corporation: Consultancy; Janssen Pharmaceuticals: Consultancy. Rifkin:Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy. Narang:Celgene: Speakers Bureau. Terebelo:Celgene: Honoraria; Jannsen: Speakers Bureau; Newland Medical Asociates: Employment. Toomey:Celgene: Consultancy. Hardin:Celgene: Membership on an entity's Board of Directors or advisory committees. Wagner:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; American Cancer Society: Other: Section editor, Cancer journal. Omel:Celgene, Takeda, Janssen: Other: Patient Advisory Committees. Srinivasan:Celgene: Employment, Equity Ownership. Liu:TechData: Consultancy. Dhalla:Celgene: Employment. Agarwal:Celgene Corporation: Employment, Equity Ownership. Abonour:BMS: Consultancy; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding.

scholarly journals Impact of Modified Thalidomide Dosing in Bortezomib/Thalidomide/Dexamethasone for Patients with Newly Diagnosed Multiple Myeloma Who Are Transplant-Eligible: A Matching-Adjusted Indirect Comparison

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4739-4739
Author(s):  
Pieter Sonneveld ◽  
Maria-Victoria Mateos ◽  
Adrián Alegre ◽  
Thierry Facon ◽  
Cyrille Hulin ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Board Of Directors ◽  
Research Funding ◽  
Indirect Comparison ◽  
Employment Equity ◽  
Advisory Committees ◽  
Post Transplant ◽  
Post Induction ◽  
Adjusted Indirect Comparison ◽  
Equity Ownership

Introduction: For patients with newly diagnosed multiple myeloma (NDMM) who are transplant-eligible, bortezomib/thalidomide/dexamethasone (VTd) is a standard of care (SoC) for induction and consolidation therapy. Clinical practice has evolved to use a modified VTd dose (VTd-mod; 100 mg thalidomide daily), which is reflected in recent treatment guidelines. As VTd-mod has become a real-world SoC, a matching-adjusted indirect comparison (MAIC) of the VTd-mod dose from recent clinical trials versus the dose included in the label (VTd-label; ramp up to 200 mg thalidomide daily) was performed to understand the effect on efficacy of modified VTd dosing for patients with NDMM who are transplant-eligible. Methods: For each outcome (overall survival [OS], progression-free survival [PFS], overall response rates [ORR] post-induction and post-transplant, and rate of peripheral neuropathy), a naïve comparison and a MAIC were performed. Data for VTd-label were obtained from the phase 3 PETHEMA/GEM study (Rosiñol L, et al. Blood. 2012;120[8]:1589-1596). Data for VTd-mod were pooled from the phase 3 CASSIOPEIA study (Moreau P, et al. Lancet. 2019;394[10192]:29-38) and the phase 2 NCT00531453 study (Ludwig H, et al. J Clin Oncol. 2013;31[2]:247-255). Patient-level data for PETHEMA/GEM and CASSIOPEIA were used to generate outcomes of interest and were validated against their respective clinical study reports; aggregate data for NCT00531453 were extracted from the primary publication. Matched baseline characteristics were age, sex, ECOG performance status, myeloma type, International Staging System (ISS) stage, baseline creatinine clearance, hemoglobin level, and platelet count. Results: Patients received VTd-mod (n = 591) or VTd-label (n = 130). After matching, baseline characteristics were similar across groups. For OS, the naïve comparison and the MAIC showed that VTd-mod was non-inferior to VTd-label (MAIC HR, 0.640 [95% CI: 0.363-1.129], P = 0.121; Figure 1A). VTd-mod significantly improved PFS versus VTd-label in the naïve comparison and MAIC (MAIC HR, 0.672 [95% CI: 0.467-0.966], P = 0.031; Figure 1B). Post-induction ORR was non-inferior for VTd-mod versus VTd-label (MAIC odds ratio, 1.781 [95% CI: 1.004-3.16], P = 0.065). Post-transplant, VTd-mod demonstrated superior ORR in both the naïve comparison and MAIC (MAIC odds ratio, 2.661 [95% CI: 1.579-4.484], P = 0.001). For rates of grade 3 or 4 peripheral neuropathy, the naïve comparison and MAIC both demonstrated that VTd-mod was non-inferior to VTd-label (MAIC rate difference, 2.4 [⁻1.7-6.49], P = 0.409). Conclusions: As naïve, indirect comparisons are prone to bias due to patient heterogeneity between studies, a MAIC can provide useful insights for clinicians and reimbursement decision-makers regarding the relative efficacy and safety of different treatments. In this MAIC, non-inferiority of VTd-mod versus VTd-label was demonstrated for OS, post-induction ORR, and peripheral neuropathy. This analysis also showed that VTd-mod significantly improved PFS and ORR post-transplant compared with VTd-label for patients with NDMM who are transplant-eligible. A limitation of this analysis is that unreported or unobserved confounding factors could not be adjusted for. Disclosures Sonneveld: Takeda: Honoraria, Research Funding; SkylineDx: Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; BMS: Honoraria; Amgen: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding. Mateos:Janssen, Celgene, Takeda, Amgen, Adaptive: Honoraria; AbbVie Inc, Amgen Inc, Celgene Corporation, Genentech, GlaxoSmithKline, Janssen Biotech Inc, Mundipharma EDO, PharmaMar, Roche Laboratories Inc, Takeda Oncology: Other: Advisory Committee; Janssen, Celgene, Takeda, Amgen, GSK, Abbvie, EDO, Pharmar: Membership on an entity's Board of Directors or advisory committees; Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Takeda Oncology.: Speakers Bureau; Amgen Inc, Janssen Biotech Inc: Other: Data and Monitoring Committee. Alegre:Celgene, Amgen, Janssen, Takeda: Membership on an entity's Board of Directors or advisory committees. Facon:Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hulin:celgene: Consultancy, Honoraria; Janssen, AbbVie, Celgene, Amgen: Honoraria. Hashim:Ingress-Health: Employment. Vincken:Janssen: Employment, Equity Ownership. Kampfenkel:Janssen: Employment, Equity Ownership. Cote:Janssen: Employment, Equity Ownership. Moreau:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria.

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

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

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

scholarly journals Role of Remission Status and Prior Transplant in Optimizing Survival Outcomes Following Allogeneic Hematopoietic Stem Transplantation (HSCT) in Patients Who Received Inotuzumab Ozogamicin (INO) for Relapsed / Refractory (R/R) Acute Lymphoblastic Leukemia (ALL)

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 886-886
Author(s):  
Partow Kebriaei ◽  
Matthias Stelljes ◽  
Daniel J. DeAngelo ◽  
Nicola Goekbuget ◽  
Hagop M. Kantarjian ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Survival Probability ◽  
Research Funding ◽  
Employment Equity ◽  
Inotuzumab Ozogamicin ◽  
Advisory Committees ◽  
Allogeneic Hsct ◽  
Post Transplant ◽  
Equity Ownership

Abstract Introduction: Attaining complete remission (CR) prior to HSCT is associated with better outcomes post-HSCT. Inotuzumab ozogamicin (INO), an anti-CD22 antibody conjugated to calicheamicin, has shown significantly higher remission rates (CR/CRi and MRD negativity) compared with standard chemotherapy (SC) in patients (pts) with R/R ALL (Kantarjian et al. N Engl J Med. 2016). Pts treated with INO were more likely to proceed to HSCT than SC, which allowed for a higher 2-yr probability of overall survival (OS) than patients receiving SC (39% vs 29%). We investigated the role of prior transplant and proceeding directly to HSCT after attaining remission from INO administration as potential factors in determining post-HSCT survival to inform when best to use INO in R/R ALL patients. Methods: The analysis population consisted of R/R ALL pts who were enrolled and treated with INO and proceeded to allogeneic HSCT as part of two clinical trials: Study 1010 is a Phase 1/2 trial (NCT01363297), while Study 1022 is the pivotal randomized Phase 3 (NCT01564784) trial. Full details of methods for both studies have been previously published (DeAngelo et al. Blood Adv. 2017). All reference to OS pertains to post-HSCT survival defined as time from HSCT to death from any cause. Results: As of March 2016, out of 236 pts administered INO in the two studies (Study 1010, n=72; Study 1022, n=164), 101 (43%) proceeded to allogeneic HSCT and were included in this analysis. Median age was 37 y (range 20-71) with 55% males. The majority of pts received INO as first salvage treatment (62%) and 85% had no prior SCT. Most pts received matched HSCTs (related = 25%; unrelated = 45%) with peripheral blood as the predominant cell source (62%). The conditioning regimens were mainly myeloablative regimens (60%) and predominantly TBI-based (62%). Dual alkylators were used in 13% of pts, while thiotepa was used in 8%. The Figure shows post-transplant survival in the different INO populations: The median OS post-HSCT for all pts (n=101) who received INO and proceeded to HSCT was 9.2 mos with a 2-yr survival probability of 41% (95% confidence interval [CI] 31-51%). In patients with first HSCT (n=86) the median OS post-HSCT was 11.8 mos with a 2-yr survival probability of 46% (95% CI 35-56%). Of note, some patients lost CR while waiting for HSCT and had to receive additional treatments before proceeding to HSCT (n=28). Those pts who went directly to first HSCT after attaining remission with no intervening additional treatment (n=73) fared best, with median OS post-HSCT not reached with a 2-yr survival probability of 51% (95% CI 39-62%). In the latter group, 59/73 (80%) attained MRD negativity, and 49/73 (67%) were in first salvage therapy. Of note, the post-HSCT 100-day survival probability was similar among the 3 groups, as shown in the Table. Multivariate analyses using Cox regression modelling confirmed that MRD negativity during INO treatment and no prior HSCT were associated with lower risk of mortality post-HSCT. Other prognostic factors associated with worse OS included older age, higher baseline LDH, higher last bilirubin measurement prior to HSCT, and use of thiotepa. Veno-occlusive disease post-transplant was noted in 19 of the 101 pts who received INO. Conclusion: Administration of INO in R/R ALL pts followed with allogeneic HSCT provided the best long-term survival benefit among those who went directly to HSCT after attaining remission and had no prior HSCT. Disclosures DeAngelo: Glycomimetics: Research Funding; Incyte: Consultancy, Honoraria; Blueprint Medicines: Honoraria, Research Funding; Takeda Pharmaceuticals U.S.A., Inc.: Honoraria; Shire: Honoraria; Pfizer Inc.: Consultancy, Honoraria, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Research Funding; BMS: Consultancy; ARIAD: Consultancy, Research Funding; Immunogen: Honoraria, Research Funding; Celgene: Research Funding; Amgen: Consultancy, Research Funding. Kantarjian: Novartis: Research Funding; Amgen: Research Funding; Delta-Fly Pharma: Research Funding; Bristol-Meyers Squibb: Research Funding; Pfizer: Research Funding; ARIAD: Research Funding. Advani: Takeda/ Millenium: Research Funding; Pfizer: Consultancy. Merchant: Pfizer: Consultancy, Research Funding. Stock: Amgen: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Wang: Pfizer: Employment, Equity Ownership. Zhang: Pfizer: Employment, Equity Ownership. Loberiza: Pfizer: Employment, Equity Ownership. Vandendries: Pfizer: Employment, Equity Ownership. Marks: Pfizer: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau.

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