scholarly journals Phase I study of MLN8237—investigational Aurora A kinase inhibitor—in relapsed/refractory multiple myeloma, Non-Hodgkin lymphoma and chronic lymphocytic leukemia

2013 ◽  
Vol 32 (3) ◽  
pp. 489-499 ◽  
Author(s):  
Kevin R. Kelly ◽  
Thomas C. Shea ◽  
André Goy ◽  
Jesus G. Berdeja ◽  
Craig B. Reeder ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Chronic Lymphocytic Leukemia ◽  
Phase I ◽  
Hodgkin Lymphoma ◽  
Phase I Study ◽  
Kinase Inhibitor ◽  
Lymphocytic Leukemia ◽  
Aurora A Kinase ◽  
Refractory Multiple Myeloma ◽  
Non Hodgkin Lymphoma

Tumor Marker CA 15-3 in Hematological Malignancies.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4329-4329
Author(s):  
Zoi Saouli ◽  
Athanasios Papadopoulos ◽  
Georgia Kaiafa ◽  
Fotios Girtovitis ◽  
Georg Charisopoulos ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Chronic Lymphocytic Leukemia ◽  
Acute Leukemia ◽  
Healthy Volunteers ◽  
Hodgkin Lymphoma ◽  
Hematological Malignancies ◽  
Myeloproliferative Disorders ◽  
Response To Therapy ◽  
Lymphocytic Leukemia ◽  
Non Hodgkin Lymphoma

Abstract Introduction: CA 15-3 is a glycoprotein expressed in several adenocarcinomas, especially of the breast. It is used to detect recurrent or metastatic disease. Elevated levels can also be found in adenocarcinomas of the ovary, lung, pancreas, and colon, and are also related to benign breast or ovarian disease, endometriosis, hepatitis, pregnancy and lactation. To our knowledge with the exception of multiple myeloma, there are no references for the significance of the CA 15-3 in hematological malignancies. Aim of our study was to evaluate the levels of CA 15-3 in patients with various hematological malignancies. Material and Methods: 84 patients with hematological malignancies were tested: MDS 27 pts, non Hodgkin lymphoma 12 pts, Hodgkin’s lymphoma 3 pts, chronic lymphocytic leukemia 13 pts, acute leukemia: 7 pts, multiple myeloma 8 pts, chronic myeloid leukemia 3 pts and other chronic myeloproliferative disorders 11 pts. 55% of the patients were men with average age of 55 (17–87) and 45% were women with average age of 52 (35–64). A group of 45 healthy volunteers’ blood donors was also tested. Immunoradiometric assay (IRMA) has been used to determine the circulating levels of the CA 15-3 marker. Results: None of the healthy volunteers had elevated Ca 15-3 levels. Among the 84 patients, 31 (36,9%) had elevated levels of CA 15-3. In MDS 10/27 pts, in Non Hodgkin Lymphoma 5/12 pts, in Hodgkin Lymphoma 1/3 pts, in Chronic Lymphocytic Leukemia 5/13 pts, in Multiple Myeloma 4/8 pts, in acute leukemia 1/7 pts and in other myeloproliferative disorders 4/11 pts. The CA 15-3 levels in hematological patients were higher than the ones in the healthy group. The difference was statistically significant (p <0.0001), (Table 1). 31 patients who where either untreated or had recurrent disease (subgroup a), had elevated CA 15-3 levels (36,8 ± 8,9 U/ml) while the rest 53 patients who were under therapy or were in remission (subgroup b) had normal levels (14,3 ± 5,2 U/ml). A statistically significant difference between the two subgroups was observed, (p <0.0001), (Table 2). The low risk MDS patients (RA, RARS) had normal level of CA 15-3, while the high risk MDS patients (RAEB, RAEB-t, CMML) had high levels of CA 15-3. Conclusions: CA 15-3 can be an indicative marker of the activity of a hematological malignancy. Also, it might be of value in monitoring hematological diseases and response to therapy. Table 1 Ca 15-3 (U/ml) Patients (total, n=84) 23 ± 12,3 Normal Subjects (n=45) 14,1 ± 4,6 p < 0.0001 Table 2 Ca 15-3 (U/ml) Subgroup a 36,8 ± 8,9 Subgroup b 14,3 ± 5,2 p < 0.0001

An Fc-Engineered Humanized Anti-CD40 Monoclonal Antibody, XmAb5485, Exhibits Potent Activity in Vitro and in Vivo against Non-Hodgkin Lymphoma, Chronic Lymphocytic Leukemia and Multiple Myeloma

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 881-881 ◽  
Author(s):  
Eugene A. Zhukovsky ◽  
Holly Horton ◽  
Matthias Peipp ◽  
Erik Pong ◽  
Matthew Bernett ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Cell Line ◽  
Hodgkin Lymphoma ◽  
Cell Lines ◽  
Lymphocytic Leukemia ◽  
Non Hodgkin Lymphoma

Abstract CD40, a transmembrane glycoprotein belonging to the tumor necrosis factor receptor family, is an attractive target for cancers of lymphoid origin since it is expressed on most mature B-cell malignancies, some early B-cell acute lymphocytic leukemias, and multiple myeloma. Finding efficient therapies for multiple myeloma (MM), chronic lymphocytic leukemia (CLL) and rituximab-refractory Non-Hodgkin Lymphoma (NHL) represents an unmet need. Several anti-CD40 antibodies, both agonistic and antagonistic, have demonstrated objective responses in early clinical NHL trials and thus validated this antigen as a target for lymphoproliferative diseases. Here we present the characterization of a novel Fc-engineered and humanized anti-CD40 antibody, XmAb®5485, that was generated using our XmAb antibody engineering technology. This antibody is highly cytotoxic against lymphoma, leukemia and multiple myeloma cell lines as well as primary cancer cells. XmAb5485 is characterized by: i) increased affinity for Fc gamma receptors (FcgR), ii) improved effector function, and iii) significantly increased antitumor potency. We investigated several direct and indirect (Fc-mediated) mechanisms of antibody-mediated cytotoxicity in vitro. The potency (EC50) of XmAb5485 in antibody-dependent cell-mediated cytotoxicity (ADCC) increased up to 150-fold relative to the native non Fc-engineered version (anti-CD40 IgG1) of the antibody in a screen of Burkitt’s lymphoma [BL], CLL and MM-derived cell lines. In the same cell lines, ADCC potency and maximal efficacy (% lysis) of XmAb5485 were also superior to that of rituximab: 74- and 1.3-fold higher in CLL, 12.5- and 1.4-fold higher in BL, and 190- and 1.9-fold higher in MM. In a MM cell line with low density of CD40 expression (~3500 per cell) XmAb5485 facilitated efficient ADCC whereas anti-CD40 IgG1 was virtually ineffective. Furthermore, using a BL cell line (Ramos) XmAb5485 displayed antibody-dependent cellular phagocytosis (ADCP) with potency and efficacy increased relative to rituximab (15- and 1.6-fold) and anti-CD40 IgG1 (5- and 1.2-fold). XmAb5485 also exhibited anti-proliferative apoptotic activity that was similar to that of rituximab. Ex vivo, XmAb5485 mediated potent ADCC of multiple primary patient-derived CLL, MCL, and plasma cell leukemia (PCL, an aggressive form of MM) cells, with substantially increased potency and efficacy relative to rituximab; in contrast, anti-CD40 IgG1 displayed minimal or no activity in these primary tumor cells. In vivo, in an established large (210–350 mm3) sc Ramos tumor xenograft model, 6 mg/kg XmAb5485 cured 80% of mice of detectable tumors and displayed statistically significant superiority over anti-CD40 IgG1. In contrast, only 7% of animals in the rituximab cohort were cured. In summary, our data suggest that XmAb5485, an anti-CD40 Fc variant antibody engineered for increased effector function, is a promising next-generation immunotherapeutic for leukemias, lymphomas, and multiple myeloma.

A Phase I Study of Arsenic Trioxide (Trisenox), Ascorbic Acid, and Bortezomib (Velcade) Combination Therapy in Patients with Relapsed/Refractory Mulitple Myeloma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5129-5129
Author(s):  
Lauren Held ◽  
Jon P. Gockerman ◽  
Louis F. Diehl ◽  
Carlos Manuel de Castro ◽  
Joseph O. Moore ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Ascorbic Acid ◽  
Phase I ◽  
Arsenic Trioxide ◽  
Patient Population ◽  
Phase I Study ◽  
Kinase Inhibitor ◽  
Standard Dose ◽  
Dependent Manner ◽  
Refractory Multiple Myeloma

Abstract Abstract 5129 Purpose: Bortezomib is a well recognized standard therapy, however it is not curative for multiple myeloma. New agents and approaches are needed to overcome resistance in multiple myeloma. Arsenic trioxde (ATO) induces apoptosis of plasma cells through a number of mechanisms, including down regulation of gene overexpression, activating cell cycle arrest by inducing p21 cyclin-dependent kinase inhibitor protein, and by triggering apoptosis through caspase-3 in a dose dependent manner. This phase I study assessed the feasibility and tolerability of concomitant administration of arsenic trioxide (ATO), ascorbic acid (AA), and bortezomib (VelcadeÔ) (AAV) in patients with relapsed/refractory multiple myeloma. Experimental Design: A standard dose of ATO (0.25 mg/kg IV infused over 1–2 hours) and AA (1g IV infused over 15 minutes after infusion of ATO) were given once weekly × 2 with an escalating dose of bortezomib (cohort 1: 1 mg/m2 or cohort 2: 1.3 mg/m2 IV bolus on days 1, 8) of a 21 day cycle). ATO was given at least 1 hour prior to bortezomib and patients were allowed up to a maximum of 6–8 cycles. Results: A total of ten patients (median age, 62 years old) were enrolled with a median follow up of survivors of 25 months. Patients had an average of 4 prior failed therapies. Seven (70%) patients were refractory to bortezomib when previously administered. Despite our patient population being heavily pre-treated, objective responses were observed, with one partial response (Cohort 2), two minimal response (Cohort 1 and 2), and one stable disease (Cohort 2). To date, three of the 10 patients are continuing maintenance therapy 13–43 months from initiating this study. Conclusion: Of the patients that completed the treatment, objective responses were observed despite suboptimal dosing and previous bortezomib treatment failure. Tolerability was observed in most patients as discontinuation was not due to treatment toxicities, but due to aggressiveness of disease. Further studies are warranted with a larger patient population to effectively determine the effectiveness of AAV in relapsed/refractory multiple myeloma. Disclosures: Rizzieri: Cephalon: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Long:Millennium: Speakers Bureau. Gasparetto:Millennium: Speakers Bureau.

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