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Leukemia & Lymphoma 2015Single-agent dacetuzumab has demonstrated antitumor activity in relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Preclinical data demonstrated improved... (Randomized Controlled Trial)
Randomized Controlled Trial
Dacetuzumab plus rituximab, ifosfamide, carboplatin and etoposide as salvage therapy for patients with diffuse large B-cell lymphoma relapsing after rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone: a randomized, double-blind, placebo-controlled phase 2b trial.
Single-agent dacetuzumab has demonstrated antitumor activity in relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Preclinical data demonstrated improved dacetuzumab antitumor activity in combination with rituximab, ± chemotherapy. We designed a phase 2b, double-blind, placebo-controlled trial to compare rituximab, ifosfamide, carboplatin and etoposide (R-ICE) + dacetuzumab with R-ICE + placebo in patients with DLBCL who relapsed after rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) (ClinicalTrials.gov #NCT00529503). The primary endpoint was complete response (CR); additional endpoints included failure-free survival and overall survival (OS). Overall, 151 patients were randomized (75 dacetuzumab, 76 placebo). No notable differences between arms in demographics or subsequent treatment parameters were observed. Cytopenias, cough and infection were more frequent with dacetuzumab. Futility analysis failed to demonstrate higher CR rates with dacetuzumab (36% dacetuzumab, 42% placebo); consequently, enrollment was stopped. Unplanned post hoc analysis showed that patients who underwent subsequent autologous stem cell transplant experienced improvement in OS (hazard ratio = 0.195, p = 0.004), which may be explained by potential immunomodulatory effects of dacetuzumab on antigen-presenting cells.
Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Cough; Cyclophosphamide; Double-Blind Method; Doxorubicin; Etoposide; Female; Humans; Ifosfamide; Kaplan-Meier Estimate; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Neoplasm Recurrence, Local; Prednisolone; Remission Induction; Rituximab; Salvage Therapy; Thrombocytopenia; Treatment Outcome; Vincristine
PubMed: 25651427
DOI: 10.3109/10428194.2015.1007504 -
Current Opinion in Investigational... Jun 2009Dacetuzumab, a humanized mAb targeting the CD40 antigen, is in development by Seattle Genetics Inc and licensee Genentech Inc for the potential treatment of...
Dacetuzumab, a humanized mAb targeting the CD40 antigen, is in development by Seattle Genetics Inc and licensee Genentech Inc for the potential treatment of hematological malignancies. The CD40 antigen is a highly expressed cell surface transmembrane protein that is present in normal B-cells. Experiments using blocking antibodies for the CD40 ligand demonstrated that CD40 signaling may play a role in the development and maintenance of B-cell hematological malignancies and some solid tumors. In vitro, dacetuzumab exhibited antitumor activity against several B-cell lymphoma and multiple myeloma (MM) cell lines, and induced direct apoptosis as well as the engagement of effective antibody-dependent cell-mediated cytotoxicity. In vivo, dacetuzumab demonstrated enhanced antitumor efficacy in combination with other mAbs and chemotherapeutic agents; many of these combinations are now being tested clinically. Early clinical trials have evaluated the pharmacokinetics, safety and efficacy of dacetuzumab monotherapy in patients with relapsed/refractory B-cell lymphomas or MM. Targeting CD40 with dacetuzumab resulted in modest antitumor activity in B-cell lymphomas and, to a lesser extent, in MM. In particular, patients with diffuse large B-cell lymphoma responded well to dacetuzumab; the drug is being pursued for this indication in phase II trials.
Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; CD40 Antigens; Cell Line, Tumor; Cell Proliferation; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Drug Evaluation, Preclinical; Hematologic Neoplasms; Humans; Lymphoma, B-Cell; Macaca fascicularis; Mice; Multiple Myeloma; Treatment Outcome; Xenograft Model Antitumor Assays
PubMed: 19513947
DOI: No ID Found -
Haematologica May 2010This first-in-human, phase I study evaluated the safety, maximum-tolerated dose, pharmacokinetics, and antitumor activity of dacetuzumab in 44 patients with advanced... (Comparative Study)
Comparative Study
This first-in-human, phase I study evaluated the safety, maximum-tolerated dose, pharmacokinetics, and antitumor activity of dacetuzumab in 44 patients with advanced multiple myeloma. Patients received intravenous dacetuzumab, either in 4 uniform weekly doses (first 4 cohorts) or using a 5-week intrapatient dose escalation schedule (7 subsequent cohorts; the last 3 cohorts received steroid pre-medication). An initial dose of 4 mg/kg dacetuzumab exceeded the maximum-tolerated dose for uniform weekly dosing. Intrapatient dose escalation with steroid pre-medication appeared effective in reducing symptoms of cytokine release syndrome and the maximum-tolerated dose with this dosing schema was 12 mg/kg/week. Adverse events potentially related to dacetuzumab included cytokine release syndrome symptoms, non-infectious ocular inflammation, and elevated hepatic enzymes. Peak dacetuzumab blood levels increased with dose. Nine patients (20%) had a best clinical response of stable disease. The observed safety profile suggested that dacetuzumab may be combined with other multiple myeloma therapies. Two combination trials are ongoing. Clinical trials gov identifier: NCT00079716.
Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; CD40 Antigens; Cohort Studies; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Inflammation; Male; Middle Aged; Multiple Myeloma
PubMed: 20133895
DOI: 10.3324/haematol.2009.008003 -
Leukemia & Lymphoma Feb 2013Dacetuzumab, a CD40-targeted, humanized antibody, mediates antitumor activity through effector cell functions and direct apoptotic signal transduction. Preclinical...
Dacetuzumab, a CD40-targeted, humanized antibody, mediates antitumor activity through effector cell functions and direct apoptotic signal transduction. Preclinical studies demonstrated synergistic activity between dacetuzumab, gemcitabine and rituximab against non-Hodgkin lymphoma in vivo. A phase 1b safety/efficacy study of dacetuzumab in combination with rituximab and gemcitabine was conducted in relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Patients received dacetuzumab at doses of 8 or 12 mg/kg IV weekly with rituximab (375 mg/m(2) IV weekly in cycle 1, then every 28 days) and gemcitabine (1000 mg/m(2) IV, days 1, 8 and 15, or days 1 and 15). Thirty-three patients with a median age of 67 years were enrolled. Common adverse events (≥ 15%) were grade 1/2 cytokine release syndrome, nausea, fatigue, thrombocytopenia, headache, decreased appetite, dyspnea, neutropenia, pyrexia, anemia, diarrhea, edema, constipation and cough. Dacetuzumab-related grade 3/4 adverse events occurred infrequently. Six of 30 evaluable patients achieved a complete response (CR) and eight a partial response (PR) per investigator assessment for an overall response rate (ORR) of 47%.
Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Female; Humans; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Pilot Projects; Recurrence; Rituximab; Treatment Outcome; Gemcitabine
PubMed: 22775314
DOI: 10.3109/10428194.2012.710328 -
Journal of Hematology & Oncology Jun 2014Patients with DLBCL who are ineligible for or have relapsed after aggressive salvage chemotherapy have a poor prognosis. CD40 is expressed on multiple B-cell neoplasms...
BACKGROUND
Patients with DLBCL who are ineligible for or have relapsed after aggressive salvage chemotherapy have a poor prognosis. CD40 is expressed on multiple B-cell neoplasms including DLBCL and is a potential target for immunotherapy. Dacetuzumab (SGN-40), a non-blocking, partial agonist, humanized IgG1, anti-CD40 monoclonal antibody, has previously demonstrated anti-lymphoma activity in a phase I study.
METHODS
A phase II study was undertaken to evaluate the rate and duration of objective responses and safety of single-agent dacetuzumab in relapsed DLBCL. Forty-six adult patients with relapsed/refractory DLBCL received up to 12 cycles of intravenous dacetuzumab using intrapatient dose-escalation to a target dose of 8 mg/kg/week in an initial 5-week cycle, followed by 4-week cycles of 8 mg/kg/week. Study endpoints included rate and duration of objective responses, safety, survival, pharmacokinetics, immunogenicity, and exploratory correlative studies.
RESULTS
Overall response rate was 9% and disease control rate (complete remission + partial remission + stable disease) was 37%. Common non-hematologic adverse events (AEs) included fatigue, headache, chills, fever, and nausea. The most frequent Grade 3-4 non-hematologic AE was deep venous thrombosis (3 patients). Grade 3-4 lymphopenia (41%), neutropenia (13%), or thrombocytopenia (19%) occurred without associated infection or bleeding. Reversible ocular events, including conjunctivitis and ocular hyperemia, occurred in 8 patients (17%). Patient-specific factors, including Fc-gamma-RIIIa polymorphism, did not appear to correlate with antitumor activity.
CONCLUSIONS
Single-agent dacetuzumab has modest activity and manageable toxicity in unselected patients with relapsed DLBCL. Combination regimens and robust methods of patient selection may be necessary for further development.
TRIAL REGISTRATION
ClinicalTrials.gov identifier NCT00435916.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; CD40 Antigens; Chills; Dose-Response Relationship, Drug; Drug Administration Schedule; Fatigue; Female; Headache; Humans; Kaplan-Meier Estimate; Lymphoma, Large B-Cell, Diffuse; Lymphopenia; Male; Middle Aged; Neoplasm Recurrence, Local; Polymorphism, Single Nucleotide; Receptors, IgG; Remission Induction; Treatment Outcome; Young Adult
PubMed: 24919462
DOI: 10.1186/1756-8722-7-44 -
Leukemia Jun 2011Non-Hodgkin lymphoma (NHL) is a genetically heterogeneous disease with several oncogenic events implicated in the transformation of normal developing B lymphocytes. The...
Non-Hodgkin lymphoma (NHL) is a genetically heterogeneous disease with several oncogenic events implicated in the transformation of normal developing B lymphocytes. The objective of this study was to elucidate the signal transduction-based antitumor mechanism(s) of action for the anti-CD40 monoclonal antibody dacetuzumab (SGN-40) in NHL. We report that dacetuzumab activates two distinct proapoptotic signaling pathways, overcoming transformation events key to the pathogenesis of NHL. Dacetuzumab-mediated CD40 signaling constitutively activated the nuclear factor-κB and mitogen-activated protein kinase signaling pathways producing the sustained downregulation of B-cell lymphoma 6 (BCL-6), an oncoprotein implicated in lymphomagenesis. Loss of BCL-6 resulted in c-Myc downregulation and activation of a transcriptional program characteristic of early B-cell maturation, concomitant with reduced proliferation and cell death. In a second mechanism, dacetuzumab signaling induced the expression of the proapoptotic p53 family member TAp63α and downstream proteins associated with the intrinsic and extrinsic apoptotic machinery. Dacetuzumab was synergistic in combination with DNA-damaging chemotherapeutic drugs, correlating with TAp63α upregulation. Furthermore, dacetuzumab augmented the activity of rituximab in combination with multiple chemotherapies in the xenograft models of NHL. The ability of dacetuzumab signaling to circumvent oncogenic events and potentiate the activity of chemotherapy regimens provides a unique therapeutic approach to NHL.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Apoptosis; Apoptosis Regulatory Proteins; Cell Transformation, Neoplastic; Drug Resistance, Neoplasm; Gene Expression Regulation; Humans; Lymphoma, Non-Hodgkin; Signal Transduction; Transcription, Genetic; Tumor Cells, Cultured
PubMed: 21394099
DOI: 10.1038/leu.2011.21 -
Leukemia & Lymphoma Feb 2010Despite advances in therapy, chronic lymphocytic leukemia remains an incurable disease and novel, effective therapies are needed. In this open-label, dose-escalation,...
Despite advances in therapy, chronic lymphocytic leukemia remains an incurable disease and novel, effective therapies are needed. In this open-label, dose-escalation, phase I study, dacetuzumab (IgG1 humanized monoclonal antibody) was administered to 12 adults, all of whom had received several prior systemic therapies (median, 4; range, 2-11). Intrapatient dose escalation (maximum weekly doses of 3-8 mg/kg) was used to diminish first-dose-related inflammatory symptoms. No dose-limiting toxicities or dose-dependent trends in adverse events (AEs) were observed. The most common AEs (in >/=2 patients) were fatigue, headache, anorexia, conjunctivitis, hyperhidrosis, and night sweats, all of which were mild or moderate. No deaths, serious AEs, or discontinuations due to AEs occurred. Although no patient achieved an objective response, five patients demonstrated stable disease after 1 cycle of therapy, with no discernable correlation between dacetuzumab dose and outcome. This modest single-agent activity may warrant further testing of dacetuzumab in combination with other chronic lymphocytic leukemia therapies.
Topics: Adult; Aged; Aged, 80 and over; Anorexia; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Conjunctivitis; Dose-Response Relationship, Drug; Fatigue; Female; Headache; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Treatment Outcome
PubMed: 20038235
DOI: 10.3109/10428190903440946 -
Clinical Cancer Research : An Official... Jul 2011Individually targeting B-cell antigens with monoclonal antibody therapeutics has improved the treatment of non-Hodgkin lymphoma (NHL). We examined if the antitumor...
PURPOSE
Individually targeting B-cell antigens with monoclonal antibody therapeutics has improved the treatment of non-Hodgkin lymphoma (NHL). We examined if the antitumor activity of rituximab, CD20-specific antibody, could be improved by simultaneously targeting CD40 with the humanized monoclonal antibody dacetuzumab (SGN-40).
EXPERIMENTAL DESIGN
Dacetuzumab was dosed with rituximab to determine the in vivo activity of this combination in a subcutaneous Ramos xenograft model of non-Hodgkin lymphoma (NHL). The effect of dacetuzumab on rituximab antibody-dependent cell mediated-cytotoxicity (ADCC), antiproliferative, and apoptotic activities were evaluated in vitro using NHL cell lines. Western blotting and flow cytometry were used to contrast the signaling pathways activated by dacetuzumab and rituximab in NHL cells.
RESULTS
The dacetuzumab-rituximab combination had significantly improved antitumor activity over the equivalent dose of rituximab in the Ramos xenograft model (P = 0.0021). Dacetuzumab did not augment rituximab-mediated ADCC activity; however, these antibodies were additive to synergistic in cell-proliferation assays and produced increased apoptosis in combination. Rituximab signaling downregulated BCL-6 oncoprotein in a cell line-specific manner, whereas dacetuzumab strongly downregulated BCL-6 in each cell line. Dacetuzumab induced expression of the proapoptotic proteins TAp63 and Fas, whereas rituximab did not affect basal expression of either protein. Finally, rituximab partially blocked dacetuzumab-mediated upregulation of the prosurvival protein BCL-x(L).
CONCLUSIONS
Targeting CD40 with dacetuzumab enhanced the antitumor activity of rituximab in cell line and xenograft NHL models. The distinct but complementary apoptotic signal transduction profiles of dacetuzumab and rituximab are an important mechanism behind the improved activity of this combination.
Topics: Animals; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Agents; Apoptosis; CD40 Antigens; Cell Line, Tumor; Cell Proliferation; Drug Synergism; Humans; Kaplan-Meier Estimate; Lymphoma, Non-Hodgkin; Mice; Mice, SCID; Rituximab; Signal Transduction; Xenograft Model Antitumor Assays
PubMed: 21610152
DOI: 10.1158/1078-0432.CCR-11-0479 -
Biochemical and Biophysical Research... Jun 2024CD40 is a member of the tumor necrosis factor receptor superfamily, and it is widely expressed on immune and non-immune cell types. The interaction between CD40 and the...
CD40 is a member of the tumor necrosis factor receptor superfamily, and it is widely expressed on immune and non-immune cell types. The interaction between CD40 and the CD40 ligand (CD40L) plays an essential function in signaling, and the CD40/CD40L complex works as an immune checkpoint molecule. CD40 has become a therapeutic target, and a variety of agonistic/antagonistic anti-CD40 monoclonal antibodies (mAbs) have been developed. To better understand the mode of action of anti-CD40 mAbs, we determined the X-ray crystal structures of dacetuzumab (agonist) and bleselumab (antagonist) in complex with the extracellular domain of human CD40, respectively. The structure reveals that dacetuzumab binds to CD40 on the top of cysteine-rich domain 1 (CRD1), which is the domain most distant from the cell surface, and it does not compete with CD40L binding. The binding interface of bleselumab spread between CRD2 and CRD1, overlapping with the binding surface of the ligand. Our results offer important insights for future structural and functional studies of CD40 and provide clues to understanding the mechanism of biological response. These data can be applied to developing new strategies for designing antibodies with more therapeutic efficacy.
Topics: Humans; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Binding Sites; CD40 Antigens; CD40 Ligand; Crystallography, X-Ray; Models, Molecular; Protein Binding; Protein Conformation
PubMed: 38657446
DOI: 10.1016/j.bbrc.2024.149969 -
Journal of Clinical Oncology : Official... Sep 2009To evaluate the safety, maximum-tolerated dose (MTD), pharmacokinetics, and antitumor activity of dacetuzumab in patients with refractory or recurrent B-cell...
PURPOSE
To evaluate the safety, maximum-tolerated dose (MTD), pharmacokinetics, and antitumor activity of dacetuzumab in patients with refractory or recurrent B-cell non-Hodgkin's lymphoma (NHL).
PATIENTS AND METHODS
In this open-label, dose-escalation phase I study, dacetuzumab was administered to six cohorts of adult patients. In the first cohort, patients received 2 mg/kg weekly for 4 weeks; in all other cohorts, an intrapatient dose-escalation schedule was used with increasing doses up to a maximum of 8 mg/kg. Patients with clinical benefit after one cycle of dacetuzumab were eligible for a second cycle.
RESULTS
In the 50 patients who received dacetuzumab, no dose dependence of adverse events (AEs) was observed. The most common AEs in >or= 20% of patients were fatigue, pyrexia, and headache; most were grade 1 or 2. Noninfectious inflammatory eye disorders occurred in 12% of patients. AEs grade >or= 3 occurred in 30% of patients and included disease progression, anemia, pleural effusion, and thrombocytopenia. Most laboratory abnormalities were grade 1 or 2; transient elevated hepatic aminotransferases occurred in 52% of patients. Two patients experienced dose-limiting toxicity: grade 3 conjunctivitis and transient vision loss in cohort (1), and grade 3 ALT elevation in cohort IV. The MTD of dacetuzumab was not established at the dose levels tested. Six objective responses were reported (one complete response, five partial responses). Tumor size decreased in approximately one third of patients.
CONCLUSION
Dacetuzumab monotherapy was well tolerated in patients with NHL in doses up to 8 mg/kg/wk. Preliminary response data are encouraging and support additional studies of dacetuzumab in this patient population.
Topics: Adult; Aged; Aged, 80 and over; Anemia; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; CD40 Antigens; Cohort Studies; Cytokines; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Fatigue; Female; Fever; Headache; Humans; Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Male; Middle Aged; Recurrence; Treatment Outcome; Young Adult
PubMed: 19636010
DOI: 10.1200/JCO.2008.21.3017